@article {pmid38649307,
year = {2024},
author = {Pang, C and Wang, R and Liu, K and Yuan, X and Ni, J and Cao, Q and Chen, Y and Dong, PL and Han, H},
title = {Serum and urine metabolomics based on UPLC-QTOF/MS reveal the effect and potential mechanism of "schisandra-evodia" herb pair in the treatment of Alzheimer's disease.},
journal = {Biomedical chromatography : BMC},
volume = {},
number = {},
pages = {e5882},
doi = {10.1002/bmc.5882},
pmid = {38649307},
issn = {1099-0801},
support = {LH2019H053//Natural Science Foundation of Heilongjiang Province/ ; 2017XY01//Heilongjiang University of Traditional Chinese Medicine Scientific Research Fund Project/ ; },
abstract = {The "schisandra-evodia" herb pair (S-E) is a herbal preparation to treat Alzheimer's disease (AD). This study aims to investigate the therapeutic efficacy and potential mechanism of S-E in AD rats, utilizing pharmacodynamic assessments and serum- and urine-based metabolomic analyses. Pharmacodynamic assessments included Morris water maze test, hematoxylin-eosin staining and immunohistochemistry experiments. The results of the study showed that the AD model was successful; the S-E significantly enhanced long-term memory and spatial learning in AD rats. Meanwhile, S-E notably ameliorated Aβ25-35-induced cognitive impairment, improved hippocampal neuron morphology, decreased Aβ deposition in the hippocampus and mitigated inflammatory damage. We then analyzed serum and urine samples using UPLC-MS/MS to identify potential biomarkers and metabolic pathways. Metabolomic analysis revealed alterations in 40 serum metabolites and 38 urine metabolites following S-E treatment, predominantly affecting pathways related to taurine and hypotaurine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism and arachidonic acid metabolism. This study elucidates the biochemical mechanism underlying AD and the metabolic pathway influenced by S-E, laying the groundwork for future clinical applications.},
}

@article {pmid38649269,
year = {2024},
author = {Murakami, R and Watanabe, H and Hashimoto, H and Kashiwagi-Hakozaki, M and Hashimoto, T and Karch, CM and , and Iwatsubo, T and Okano, H},
title = {Inhibitory roles of Apolipoprotein E Christchurch astrocytes in curbing tau propagation using human pluripotent stem cell-derived models.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1709-23.2024},
pmid = {38649269},
issn = {1529-2401},
abstract = {Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.Significance Statement Alzheimer's disease (AD) is a degenerative disease that causes cognitive decline. Familial AD is a severe form caused by mutations in the PSEN1, PSEN2, or APP genes. One carrier of the PSEN1 mutation did not develop dementia. This carrier also had a rare variant of the APOE gene, the Christchurch variant. The APOE Christchurch variant may protect against familial AD. The mechanism of this protection is not fully understood. In the present study, we have successfully demonstrated that the APOE Christchurch variant suppresses the propagation of tau and exhibits a diminished capacity to convert native astrocytes into reactive astrocytes. These significant findings contribute novel insights to the field of the APOE gene and AD research.},
}

@article {pmid38648920,
year = {2024},
author = {Reid, GA and Darvesh, S},
title = {Interaction of Exogenous Acetylcholinesterase and Butyrylcholinesterase with Amyloid-β Plaques in Human Brain Tissue.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111012},
doi = {10.1016/j.cbi.2024.111012},
pmid = {38648920},
issn = {1872-7786},
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are associated with amyloid-β (Aβ) plaques and exhibit altered biochemical properties in human Alzheimer's disease (AD), as well as in the transgenic 5XFAD mouse model of AD amyloidosis. In the brains of the 5XFAD mouse model devoid of BChE enzyme (5XFAD/BChE-KO), incubation of tissue sections with exogenous BChE purified from human plasma (pl-BChE) leads to its association with Aβ plaques and its biochemical properties are comparable to those reported for endogenous BChE associated with plaques in both human AD and in 5XFAD mouse brain tissue. We sought to determine whether these observations in 5XFAD/BChE-KO mice also apply to human brain tissues. To do so, endogenous ChE activity in human AD brain tissue sections was quenched with 50% aqueous acetonitrile (MeCNaq) leaving the tissue intact for further studies. Quenched sections were then incubated with recombinant AChE (r-AChE) or pl-BChE and stained for each enzymes' activity. Exogenous r-AChE or pl-BChE became associated with Aβ plaques, and when bound, had properties that were comparable to the endogenous ChE enzymes associated with plaques in AD brain tissues without acetonitrile treatment. These findings in human AD brain tissue extend previous observations in the 5XFAD/BChE-KO mouse model and demonstrate that exogenously applied r-AChE and pl-BChE have high affinity for Aβ plaques in human brain tissues. This association alters the biochemical properties of these enzymes, most likely due a conformational change. If incorporation of AChE and BChE in Aβ plaques facilitates AD pathogenesis, blocking this association could lead to disease-modifying approaches to AD. This work provides a method to study the mechanism of AChE and BChE interaction with Aβ plaque pathology in post-mortem human brain tissue.},
}

@article {pmid38648267,
year = {2024},
author = {Salvador, AFM and Abduljawad, N and Kipnis, J},
title = {Meningeal Lymphatics in Central Nervous System Diseases.},
journal = {Annual review of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-neuro-113023-103045},
pmid = {38648267},
issn = {1545-4126},
abstract = {Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous system (CNS) fluid exchange, waste clearance, immune cell trafficking, and immune privilege. Meningeal lymphatics have also been demonstrated to functionally modify the outcome of neurological disorders and their responses to treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review, we discuss recent evidence of the contribution of meningeal lymphatics to neurological diseases, as well as the available experimental methods for manipulating meningeal lymphatics in these conditions. Finally, we also provide a discussion of the pressing questions and challenges in utilizing meningeal lymphatics as a prime target for CNS therapeutic intervention and possibly drug delivery for brain disorders.},
}

@article {pmid38647433,
year = {2024},
author = {Mousavi, H and Rimaz, M and Zeynizadeh, B},
title = {Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00055},
pmid = {38647433},
issn = {1948-7193},
abstract = {Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2[(G2019S)], hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.},
}

@article {pmid38647399,
year = {2024},
author = {Lin, RR and Jin, LL and Xue, YY and Zhang, ZS and Huang, HF and Chen, DF and Liu, Q and Mao, ZW and Wu, ZY and Tao, QQ},
title = {Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2306675},
doi = {10.1002/advs.202306675},
pmid = {38647399},
issn = {2198-3844},
support = {2021ZD0201103//Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects/ ; 2021ZD0201803//Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects/ ; 2024SSYS0018//Key R&D Program of Zhejiang Province/ ; LBY21H090003//Natural Science Foundation of Zhejiang Province/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; },
abstract = {The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.},
}

@article {pmid38646507,
year = {2024},
author = {Zhang, X and Zhu, Z and Huang, Y and Shang, X and O'Brien, TJ and Kwan, P and Ha, J and Wang, W and Liu, S and Zhang, X and Kiburg, K and Bao, Y and Wang, J and Yu, H and He, M and Zhang, L},
title = {Shared genetic aetiology of Alzheimer's disease and age-related macular degeneration by APOC1 and APOE genes.},
journal = {BMJ neurology open},
volume = {6},
number = {1},
pages = {e000570},
pmid = {38646507},
issn = {2632-6140},
abstract = {BACKGROUND: Alzheimer's disease (AD) and age-related macular degeneration (AMD) share similar pathological features, suggesting common genetic aetiologies between the two. Investigating gene associations between AD and AMD may provide useful insights into the underlying pathogenesis and inform integrated prevention and treatment for both diseases.

METHODS: A stratified quantile-quantile (QQ) plot was constructed to detect the pleiotropy among AD and AMD based on genome-wide association studies data from 17 008 patients with AD and 30 178 patients with AMD. A Bayesian conditional false discovery rate-based (cFDR) method was used to identify pleiotropic genes. UK Biobank was used to verify the pleiotropy analysis. Biological network and enrichment analysis were conducted to explain the biological reason for pleiotropy phenomena. A diagnostic test based on gene expression data was used to predict biomarkers for AD and AMD based on pleiotropic genes and their regulators.

RESULTS: Significant pleiotropy was found between AD and AMD (significant leftward shift on QQ plots). APOC1 and APOE were identified as pleiotropic genes for AD-AMD (cFDR <0.01). Network analysis revealed that APOC1 and APOE occupied borderline positions on the gene co-expression networks. Both APOC1 and APOE genes were enriched on the herpes simplex virus 1 infection pathway. Further, machine learning-based diagnostic tests identified that APOC1, APOE (areas under the curve (AUCs) >0.65) and their upstream regulators, especially ZNF131, ADNP2 and HINFP, could be potential biomarkers for both AD and AMD (AUCs >0.8).

CONCLUSION: In this study, we confirmed the genetic pleiotropy between AD and AMD and identified APOC1 and APOE as pleiotropic genes. Further, the integration of multiomics data identified ZNF131, ADNP2 and HINFP as novel diagnostic biomarkers for AD and AMD.},
}

@article {pmid38646460,
year = {2024},
author = {Shaheen, H and Melnik, R and Singh, S and , },
title = {Data-driven Stochastic Model for Quantifying the Interplay Between Amyloid-beta and Calcium Levels in Alzheimer's Disease.},
journal = {Statistical analysis and data mining},
volume = {17},
number = {2},
pages = {},
pmid = {38646460},
issn = {1932-1864},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {The abnormal aggregation of extracellular amyloid-β(Aβ) in senile plaques resulting in calcium Ca+2 dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving Aβ deposition and Ca+2 dysregulation. Importantly, synaptic impairments, neuronal loss, and cognitive failure in AD patients are all related to the buildup of intraneuronal Aβ accumulation. Moreover, increasing evidence show a feed-forward loop between Aβ and Ca+2 levels, i.e. Aβ disrupts neuronal Ca+2 levels, which in turn affects the formation of Aβ. To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between Aβ and Ca+2 using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modelling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi-state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from 2-year visits for AD patients, we employ this method to investigate the interplay between Aβ and Ca+2 levels at various disease development phases. Incorporating the ADNI data in our physics-based Bayesian model, we discovered that a sufficiently large disruption in either Aβ metabolism or intracellular Ca+2 homeostasis causes the relative growth rate in both Ca+2 and Aβ, which corresponds to the development of AD. The imbalance of Ca+2 ions causes Aβ disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of Ca+2 ion transportation and deposition. This suggests that altering the Ca+2 balance or the balance between Aβ and Ca+2 by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy.},
}

@article {pmid38645989,
year = {2024},
author = {Peng, Y and Zhou, C},
title = {Network Pharmacology and Molecular Docking Identify the Potential Mechanism and Therapeutic Role of Scutellaria baicalensis in Alzheimer's Disease.},
journal = {Drug design, development and therapy},
volume = {18},
number = {},
pages = {1199-1219},
pmid = {38645989},
issn = {1177-8881},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Scutellaria baicalensis/chemistry ; Humans ; *Molecular Docking Simulation ; *Network Pharmacology ; Drugs, Chinese Herbal/pharmacology/chemistry ; STAT3 Transcription Factor/metabolism/antagonists & inhibitors ; Plant Extracts/pharmacology/chemistry ; },
abstract = {AIM: Scutellaria baicalensis, a traditional Chinese medicinal herb renowned for its anti-inflammatory, antioxidant, and anti-tumor properties, has shown promise in alleviating cognitive impairment associated with Alzheimer's disease. Nonetheless, the exact neuroprotective mechanism of Scutellaria baicalensis against Alzheimer's disease remains unclear. In this study, network pharmacology was employed to explore the possible mechanisms by which Scutellaria baicalensis protects against Alzheimer's disease.

METHODS: The active compounds of Scutellaria baicalensis were retrieved from the TCMSP database, and their corresponding targets were identified. Alzheimer's disease-related targets were obtained through searches in the GeneCards and OMIM databases. Cytoscape 3.6.0 software was utilized to construct a regulatory network illustrating the "active ingredient-target" relationships. Subsequently, the target genes affected by Scutellaria baicalensis in the context of Alzheimer's disease were input into the String database to establish a PPI network. GO analysis and KEGG analysis were conducted using the DAVID database to predict the potential pathways associated with these key targets. Following this, the capacity of these active ingredients to bind to core targets was confirmed through molecular docking. In vitro experiments were then carried out for further validation.

RESULTS: A total of 36 active ingredients from Scutellaria baicalensis were screened out, which corresponded to 365 targets. Molecular docking results demonstrated the robust binding abilities of Baicalein, Wogonin, and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone to key target proteins (SRC, PIK3R1, and STAT3). In vitro experiments showed that the active components of Scutellaria baicalensis can inhibit STAT3 expression by downregulating the PIK3R1/SRC pathway in Neuro 2A cells.

CONCLUSION: In summary, these findings collectively suggest that Scutellaria baicalensis holds promise as a viable treatment option for Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/metabolism
*Scutellaria baicalensis/chemistry
Humans
*Molecular Docking Simulation
*Network Pharmacology
Drugs, Chinese Herbal/pharmacology/chemistry
STAT3 Transcription Factor/metabolism/antagonists & inhibitors
Plant Extracts/pharmacology/chemistry

@article {pmid38645748,
year = {2024},
author = {Yap, LE and Hunt, JE and Turner, RS},
title = {Aging as a target for the prevention and treatment of Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1376104},
pmid = {38645748},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD.},
}

@article {pmid38645276,
year = {2024},
author = {Okafor, M and Champomier, O and Raibaut, L and Ozkan, S and El Kholti, N and Ory, S and Chasserot-Golaz, S and Gasman, S and Hureau, C and Faller, P and Vitale, N},
title = {Restoring cellular copper homeostasis in Alzheimer disease: a novel peptide shuttle is internalized by an ATP-dependent endocytosis pathway involving Rab5- and Rab14-endosomes.},
journal = {Frontiers in molecular biosciences},
volume = {11},
number = {},
pages = {1355963},
pmid = {38645276},
issn = {2296-889X},
abstract = {CPPs, or Cell-Penetrating Peptides, offer invaluable utility in disease treatment due to their ability to transport various therapeutic molecules across cellular membranes. Their unique characteristics, such as biocompatibility and low immunogenicity, make them ideal candidates for delivering drugs, genes, or imaging agents directly into cells. This targeted delivery enhances treatment efficacy while minimizing systemic side effects. CPPs exhibit versatility, crossing biological barriers and reaching intracellular targets that conventional drugs struggle to access. This capability holds promise in treating a wide array of diseases, including cancer, neurodegenerative disorders, and infectious diseases, offering a potent avenue for innovative and targeted therapies, yet their precise mechanism of cell entry is far from being fully understood. In order to correct Cu dysregulation found in various pathologies such as Alzheimer disease, we have recently conceived a peptide Cu(II) shuttle, based on the αR5W4 CPP, which, when bound to Cu(II), is able to readily enter a neurosecretory cell model, and release bioavailable Cu in cells. Furthermore, this shuttle has the capacity to protect cells in culture against oxidative stress-induced damage which occurs when Cu binds to the Aβ peptide. The aim of this study was therefore to characterize the cell entry route used by this shuttle and determine in which compartment Cu is released. Pharmacological treatments, siRNA silencing and colocalization experiments with GFP-Rab fusion proteins, indicate that the shuttle is internalized by an ATP-dependent endocytosis pathway involving both Rab5 and Rab14 endosomes route and suggest an early release of Cu from the shuttle.},
}

@article {pmid38645234,
year = {2024},
author = {Heavener, K and Kabra, K and Yidenk, M and Bradshaw, E},
title = {IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.08.588607},
pmid = {38645234},
abstract = {The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer's disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta plaques in the brain. While P2RX7 is thought to play a role in neurodegenerative diseases, how it modulates pathology and disease progression is not well understood. Here, we utilize a human monocyte-derived microglia-like cell (MDMi) model to interrogate P2RX7 activation and downstream consequences on microglia function. By using MDMi derived from human donors, we can examine how human donor variation impacts microglia function. We assessed P2RX7-driven IL1β and IL18 production and amyloid-beta peptide 1-42 (Aβ1-42) uptake levels. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression. This upregulation of cytokine gene expression is blocked with the A740003 P2RX7 antagonist. We find that high extracellular ATP conditions also reduced MDMi capacity for Aβ1-42 uptake, and this loss of function is prevented through A740003 inhibition of P2RX7. In addition, pretreatment of MDMi with IL-1RA limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Aβ1-42 uptake was higher with IL-1RA pretreatment compared to ATP treatment alone, suggesting P2RX7 regulates phagocytic engulfment through IL-1 signaling. Overall, our results demonstrate that P2RX7 is a key response protein for high extracellular ATP in human microglia-like cells, and its function can be modulated by IL-1 signaling. This work opens the door to future studies examining anti-IL-1 biologics to increase the clearance of amyloid-beta.},
}

@article {pmid38644825,
year = {2024},
author = {Patil, N and Dhariwal, R and Mohammed, A and Wei, LS and Jain, M},
title = {Network pharmacology-based approach to elucidate the pharmacologic mechanisms of natural compounds from Dictyostelium discoideum for Alzheimer's disease treatment.},
journal = {Heliyon},
volume = {10},
number = {8},
pages = {e28852},
pmid = {38644825},
issn = {2405-8440},
abstract = {Alzheimer's disease (AD) is increasingly becoming a major public health concern in our society. While many studies have explored the use of natural polyketides, alkaloids, and other chemical components in AD treatment, there is an urgent need to clarify the concept of multi-target treatment for AD. This study focuses on using network pharmacology approach to elucidate how secondary metabolites from Dictyostelium discoideum affect AD through multi-target or indirect mechanisms. The secondary metabolites produced by D. discoideum during their development were obtained from literature sources and PubChem. Disease targets were selected using GeneCards, DisGeNET, and CTD databases, while compound-based targets were identified through Swiss target prediction and Venn diagrams were used to find intersections between these targets. A network depicting the interplay among disease, drugs, active ingredients, and key target proteins (PPI network) was formed utilizing the STRING (Protein-Protein Interaction Networks Functional Enrichment Analysis) database. To anticipate the function and mechanism of the screened compounds, GO and KEGG enrichment analyses were conducted and visually presented using graphs and bubble charts. After the screening phase, the top interacting targets in the PPI network and the compound with the most active target were chosen for subsequent molecular docking and molecular dynamic simulation studies. This study identified nearly 50 potential targeting genes for each of the screened compounds and revealed multiple signaling pathways. Among these pathways, the inflammatory pathway stood out. COX-2, a receptor associated with neuroinflammation, showed differential expression in various stages of AD, particularly in pyramidal neurons during the early stages of the disease. This increase in COX-2 expression is likely induce by higher levels of IL-1, which is associated with neuritic plaques and microglial cells in AD. Molecular docking investigations demonstrated a strong binding interaction between the terpene compound PQA-11 and the neuroinflammatory receptor COX2, with a substantial binding affinity of -8.4 kcal/mol. Subsequently, a thorough analysis of the docked complex (COX2-PQA11) through Molecular Dynamics Simulation showed lower RMSD, minimal RMSF fluctuations, and a reduced total energy of -291.35 kJ/mol compared to the standard drug. These findings suggest that the therapeutic effect of PQA-11 operates through the inflammatory pathway, laying the groundwork for further in-depth research into the role of secondary metabolites in AD treatment.},
}

@article {pmid38644711,
year = {2024},
author = {Shanaida, M and Lysiuk, R and Mykhailenko, O and Hudz, N and Abdulsalam, A and Gontova, T and Oleshchuk, O and Ivankiv, Y and Shanaida, V and Lytkin, D and Bjørklund, G},
title = {Alpha-lipoic Acid: An Antioxidant with Anti-Aging Properties for Disease Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673300496240416114827},
pmid = {38644711},
issn = {1875-533X},
abstract = {The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo, and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging.},
}

@article {pmid38644708,
year = {2024},
author = {Patwekar, M and Patwekar, F and Khan, S and Sharma, R and Kumar, D},
title = {Navigating the Alzheimer's Treatment Landscape: Unraveling Amyloid-Beta Complexities and Pioneering Precision Medicine Approaches.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266295495240415114919},
pmid = {38644708},
issn = {1873-4294},
abstract = {A variety of cutting-edge methods and good knowledge of the illness's complex causes are causing a sea change in the field of Alzheimer's Disease (A.D.) research and treatment. Precision medicine is at the vanguard of this change, where individualized treatment plans based on genetic and biomarker profiles give a ray of hope for customized therapeutics. Combination therapies are becoming increasingly popular as a way to address the multifaceted pathology of Alzheimer's by simultaneously attacking Aβ plaques, tau tangles, neuroinflammation, and other factors. The article covers several therapeutic design efforts, including BACE inhibitors, gamma- secretase modulators, monoclonal antibodies (e.g., Aducanumab and Lecanemab), and anti- Aβ vaccinations. While these techniques appear promising, clinical development faces safety concerns and uneven efficacy. To address the complicated Aβ pathology in Alzheimer's disease, a multimodal approach is necessary. The statement emphasizes the continued importance of clinical trials in addressing safety and efficacy concerns. Looking ahead, it suggests that future treatments may take into account genetic and biomarker traits in order to provide more personalized care. Therapies targeting Aβ, tau tangles, neuroinflammation, and novel drug delivery modalities are planned. Nanoparticles and gene therapies are only two examples of novel drug delivery methods that have the potential to deliver treatments more effectively, with fewer side effects, and with better therapeutic results. In addition, medicines that target tau proteins in addition to Aβ are in the works. Early intervention, based on precise biomarkers, is a linchpin of Alzheimer's care, emphasizing the critical need for detecting the disease at its earliest stages. Lifestyle interventions, encompassing diet, exercise, cognitive training, and social engagement, are emerging as key components in the fight against cognitive decline. Data analytics and art are gaining prominence as strategies to mitigate the brain's inflammatory responses. To pool knowledge and resources in the fight against Alzheimer's, international cooperation between scientists, doctors, and pharmaceutical companies is still essential. In essence, a complex, individualized, and collaborative strategy will characterize Alzheimer's research and therapy in the future. Despite obstacles, these encouraging possibilities show the ongoing commitment of the scientific and medical communities to combat A.D. head-on, providing a glimmer of hope to the countless people and families touched by this savage sickness.},
}

@article {pmid38644578,
year = {2024},
author = {Yao, Q and Long, C and Yi, P and Zhang, G and Wan, W and Rao, X and Ying, J and Liang, W and Hua, F},
title = {C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.},
journal = {CNS neuroscience & therapeutics},
volume = {30},
number = {4},
pages = {e14721},
pmid = {38644578},
issn = {1755-5949},
support = {jxsq2019201023//Jiangxi Province "Double Thousand Plan"/ ; 82060219//National Natural Science Foundation of China/ ; 82271234//National Natural Science Foundation of China/ ; 20212ACB216009//Natural Science Foundation of Jiangxi Province/ ; 20212BAB216048//Natural Science Foundation of Jiangxi Province/ ; 2019YNTD12003//Youth Team Project of the Second Affiliated Hospital of Nanchang University/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; *Disease Progression ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.

AIMS: Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.

METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.

RESULTS: Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).

DISCUSSION: The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).

CONCLUSION: The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics
*Disease Progression
Animals
Amyloid beta-Peptides/metabolism

@article {pmid38643565,
year = {2024},
author = {Cai, Z and Yang, Z and Li, H and Fang, Y},
title = {Research progress of PROTACs for neurodegenerative diseases therapy.},
journal = {Bioorganic chemistry},
volume = {147},
number = {},
pages = {107386},
doi = {10.1016/j.bioorg.2024.107386},
pmid = {38643565},
issn = {1090-2120},
abstract = {Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.},
}

@article {pmid38643562,
year = {2024},
author = {Sharma, V and Chander Sharma, P and Reang, J and Yadav, V and Kumar Tonk, R and Majeed, J and Sharma, K},
title = {Impact of GSK-3β and CK-1δ on Wnt signaling pathway in alzheimer disease: A dual target approach.},
journal = {Bioorganic chemistry},
volume = {147},
number = {},
pages = {107378},
doi = {10.1016/j.bioorg.2024.107378},
pmid = {38643562},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is an enigmatic neurological illness that offers few treatment options. Recent exploration has highlighted the crucial connection of the Wnt signaling pathway in AD pathogenesis, shedding light on potential therapeutic targets. The present study focuses on the dual targeting of glycogen synthase kinase-3β (GSK-3β) and casein kinase-1δ (CK-1δ) within the framework of the Wnt signaling pathway as a possible technique for AD intervention. GSK-3β and CK-1δ are multifunctional kinases known for their roles in tau hyperphosphorylation, amyloid processing, and synaptic dysfunction, all of which are major hallmarks of Alzheimer's disease. They are intricately linked to Wnt signaling, which plays a pivotal part in sustaining neuronal function and synaptic plasticity. Dysregulation of the Wnt pathway in AD contributes to cognitive decline and neurodegeneration. This review delves into the molecular mechanisms by which GSK-3β and CK-1δ impact the Wnt signaling pathway, elucidating their roles in AD pathogenesis. We discuss the potential of small-molecule inhibitors along with their SAR studies along with the multi-targetd approach targeting GSK-3β and CK-1δ to modulate Wnt signaling and mitigate AD-related pathology. In summary, the dual targeting of GSK-3β and CK-1δ within the framework of the Wnt signaling pathway presents an innovative and promising avenue for future AD therapies, offering new hope for patients and caregivers in the quest to combat this challenging condition.},
}

@article {pmid38643230,
year = {2024},
author = {Jing, X and Wang, L and Song, M and Geng, H and Li, W and Huo, Y and Huang, A and Wang, X and An, C},
title = {Serum neurofilament light chain and inflammatory cytokines as biomarkers for early detection of mild cognitive impairment.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {9072},
pmid = {38643230},
issn = {2045-2322},
support = {ZF2024136//The government funded clinical medicine excellent talents training project of Hebei Province/ ; 199477138G//the Special Fund Project of the Central Government to Guide the Local Science and Technology Development of Hebei Province/ ; SG2021189//Science and Technology Program of Hebei Province/ ; },
mesh = {Humans ; Cross-Sectional Studies ; Intermediate Filaments ; *Alzheimer Disease ; Neurofilament Proteins ; *Cognitive Dysfunction/diagnosis ; Biomarkers ; tau Proteins ; Amyloid beta-Peptides ; },
abstract = {To investigate the association between serum neurofilament light chain (NfL) levels, inflammatory cytokines, and cognitive function to assess their utility in the early detection of mild cognitive impairment (MCI). We conducted a cross-sectional study involving 157 community-dwelling individuals aged 55 years and above, categorized into healthy controls, MCI, and probable Alzheimer's disease (AD). Serum levels of NfL, inflammatory cytokines, and AD pathology markers were measured using enzyme-linked immunosorbent assay (ELISA). Correlations between these biomarkers and cognitive function were analyzed, and the diagnostic performance of the cognitive assessment scales and serum biomarker concentrations was evaluated using receiver operating characteristic (ROC) curve analysis. Serum NfL levels were significantly elevated in MCI and probable AD groups compared to healthy controls. Positive correlations were found between serum NfL and inflammatory cytokines IL-1β, IL-6, and Aβ40. Combining serum NfL with p-tau217 and the Boston Naming Test significantly enhanced the predictive accuracy for MCI. However, combining serum NfL with inflammatory markers did not improve MCI prediction accuracy. Elevated serum NfL is associated with cognitive impairment and inflammatory markers, suggesting its potential as a peripheral serum biomarker for MCI detection. The combination of serum NfL with p-tau217 and cognitive tests could offer a more accurate prediction of MCI, providing new insights for AD treatment strategies.},
}

Humans
Cross-Sectional Studies
Intermediate Filaments
*Alzheimer Disease
Neurofilament Proteins
*Cognitive Dysfunction/diagnosis
Biomarkers
tau Proteins
Amyloid beta-Peptides

@article {pmid38642715,
year = {2024},
author = {Tong, B and Ba, Y and Li, Z and Yang, C and Su, K and Qi, H and Zhang, D and Liu, X and Wu, Y and Chen, Y and Ling, J and Zhang, J and Yu, P and Yin, X},
title = {Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106505},
doi = {10.1016/j.nbd.2024.106505},
pmid = {38642715},
issn = {1095-953X},
abstract = {Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features of AD are memory decline and cognitive dysfunction, while PD mainly manifests as motor dysfunction such as limb tremors, muscle rigidity abnormalities, and slow gait. Abnormalities in cholesterol, sphingolipid, and glycerophospholipid metabolism have been demonstrated to directly exacerbate the progression of AD by stimulating Aβ deposition and tau protein tangles. Indirectly, abnormal lipids can increase the burden on brain vasculature, induce insulin resistance, and affect the structure of neuronal cell membranes. Abnormal lipid metabolism leads to PD through inducing accumulation of α-syn, dysfunction of mitochondria and endoplasmic reticulum, and ferroptosis. Great progress has been made in targeting lipid metabolism abnormalities for the treatment of AD and PD in recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, and monoclonal antibodies targeting apolipoprotein E (ApoE). This review comprehensively summarizes the involvement of dysregulated lipid metabolism in the pathogenesis of AD and PD, the application of Lipid Monitoring, and emerging lipid regulatory drug targets. A better understanding of the lipidological bases of AD and PD may pave the way for developing effective prevention and treatment methods for neurodegenerative disorders.},
}

@article {pmid38642702,
year = {2024},
author = {Cheng, J and Liang, T and Xie, XQ and Feng, Z and Meng, L},
title = {A new era of antibody discovery: an in-depth review of AI-driven approaches.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {103984},
doi = {10.1016/j.drudis.2024.103984},
pmid = {38642702},
issn = {1878-5832},
abstract = {Given their high affinity and specificity for a range of macromolecules, antibodies are widely used in the treatment of autoimmune diseases, cancers, inflammatory diseases, and Alzheimer's disease (AD). Traditional experimental methods are time-consuming, expensive, and labor-intensive. Recent advances in artificial intelligence (AI) technologies provide complementary methods that can reduce the time and costs required for antibody design by minimizing failures and increasing the success rate of experimental tests. In this review, we scrutinize the plethora of AI-driven methodologies that have been deployed over the past 4 years for modeling antibody structures, predicting antibody-antigen interactions, optimizing antibody affinity, and generating novel antibody candidates. We also briefly address the challenges faced in integrating AI-based models with traditional antibody discovery pipelines and highlight the potential future directions in this burgeoning field.},
}

@article {pmid38641599,
year = {2024},
author = {Ackmann, J and Brüge, A and Gotina, L and Lim, S and Jahreis, K and Vollbrecht, AL and Kim, YK and Pae, AN and Labus, J and Ponimaskin, E},
title = {Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R.},
journal = {Cell communication and signaling : CCS},
volume = {22},
number = {1},
pages = {233},
pmid = {38641599},
issn = {1478-811X},
support = {StrucMed-Scholarship//Hannover Biomedical Research School - Graduate School of Excellence/ ; StrucMed-Scholarship//Hannover Biomedical Research School - Graduate School of Excellence/ ; StrucMed-Scholarship//Hannover Biomedical Research School - Graduate School of Excellence/ ; KSC-2022-CRE-0435//Korea Institute of Science and Technology Information (KISTI-HPC)/ ; KSC-2022-CRE-0435//Korea Institute of Science and Technology Information (KISTI-HPC)/ ; 2E32161//Korea Institute Science and Technology (KIST) institutional Program/ ; 2E32161//Korea Institute Science and Technology (KIST) institutional Program/ ; LA4465//Deutsche Forschungsgemeinschaft/ ; PO732//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Cyclin-Dependent Kinase 5/metabolism ; Phosphorylation ; *Alzheimer Disease/metabolism ; Signal Transduction ; Receptors, Serotonin/metabolism ; },
abstract = {BACKGROUND: Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology.

METHODS: Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex.

RESULTS: We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model.

CONCLUSIONS: Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer's disease.},
}

Humans
*Cyclin-Dependent Kinase 5/metabolism
Phosphorylation
*Alzheimer Disease/metabolism
Signal Transduction
Receptors, Serotonin/metabolism

@article {pmid38641585,
year = {2024},
author = {Hao, X and Abeysinghe, R and Zheng, F and Schulz, PE and , and Cui, L},
title = {Mapping of Alzheimer's disease related data elements and the NIH Common Data Elements.},
journal = {BMC medical informatics and decision making},
volume = {24},
number = {Suppl 3},
pages = {103},
pmid = {38641585},
issn = {1472-6947},
support = {R21AG068994/AG/NIA NIH HHS/United States ; R01NS116287/NS/NINDS NIH HHS/United States ; },
mesh = {United States/epidemiology ; Humans ; *Alzheimer Disease/diagnostic imaging/epidemiology ; Common Data Elements ; Neuroimaging ; National Institutes of Health (U.S.) ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a devastating disease that destroys memory and other cognitive functions. There has been an increasing research effort to prevent and treat AD. In the US, two major data sharing resources for AD research are the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI); Additionally, the National Institutes of Health (NIH) Common Data Elements (CDE) Repository has been developed to facilitate data sharing and improve the interoperability among data sets in various disease research areas.

METHOD: To better understand how AD-related data elements in these resources are interoperable with each other, we leverage different representation models to map data elements from different resources: NACC to ADNI, NACC to NIH CDE, and ADNI to NIH CDE. We explore bag-of-words based and word embeddings based models (Word2Vec and BioWordVec) to perform the data element mappings in these resources.

RESULTS: The data dictionaries downloaded on November 23, 2021 contain 1,195 data elements in NACC, 13,918 in ADNI, and 27,213 in NIH CDE Repository. Data element preprocessing reduced the numbers of NACC and ADNI data elements for mapping to 1,099 and 7,584 respectively. Manual evaluation of the mapping results showed that the bag-of-words based approach achieved the best precision, while the BioWordVec based approach attained the best recall. In total, the three approaches mapped 175 out of 1,099 (15.92%) NACC data elements to ADNI; 107 out of 1,099 (9.74%) NACC data elements to NIH CDE; and 171 out of 7,584 (2.25%) ADNI data elements to NIH CDE.

CONCLUSIONS: The bag-of-words based and word embeddings based approaches showed promise in mapping AD-related data elements between different resources. Although the mapping approaches need further improvement, our result indicates that there is a critical need to standardize CDEs across these valuable AD research resources in order to maximize the discoveries regarding AD pathophysiology, diagnosis, and treatment that can be gleaned from them.},
}

United States/epidemiology
Humans
*Alzheimer Disease/diagnostic imaging/epidemiology
Common Data Elements
Neuroimaging
National Institutes of Health (U.S.)

@article {pmid38640313,
year = {2024},
author = {Chen, Y and Lai, M and Tao, M},
title = {Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.},
journal = {Medicine},
volume = {103},
number = {16},
pages = {e37799},
pmid = {38640313},
issn = {1536-5964},
mesh = {Humans ; *Alzheimer Disease/drug therapy/chemically induced ; Donepezil/therapeutic use ; Galantamine/therapeutic use ; Memantine/therapeutic use ; Molecular Docking Simulation ; Cholinesterase Inhibitors/therapeutic use ; Rivastigmine/therapeutic use ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial.

OBJECTIVE: The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis.

METHODS: We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results.

RESULTS: All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs.

CONCLUSION: ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.},
}

Humans
*Alzheimer Disease/drug therapy/chemically induced
Donepezil/therapeutic use
Galantamine/therapeutic use
Memantine/therapeutic use
Molecular Docking Simulation
Cholinesterase Inhibitors/therapeutic use
Rivastigmine/therapeutic use

@article {pmid38640161,
year = {2024},
author = {Zhang, Z and Lim, MJR},
title = {Incident Dementia After Spontaneous Intracerebral Hemorrhage.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-240111},
pmid = {38640161},
issn = {1875-8908},
abstract = {Post-stroke cognitive impairment and dementia (PSCID) is a complication that affects long-term functional outcomes after stroke. Studies on dementia after long-term follow-up in stroke have focused predominantly on ischemic stroke, which may be different from the development of dementia after spontaneous intracerebral hemorrhage (ICH). In this review, we summarize the existing data and hypotheses on the development of dementia after spontaneous ICH, review the management of post-ICH dementia, and suggest areas for future research. Dementia after spontaneous ICH has a cumulative incidence of up to 32.0-37.4% at 5 years post-ICH. Although the pathophysiology of post-ICH dementia has not been fully understood, two main theoretical frameworks can be considered: 1) the triggering role of ICH (both primary and secondary brain injury) in precipitating cognitive decline and dementia; and 2) the contributory role of pre-existing brain pathology (including small vessel disease and neurodegenerative pathology), reduced cognitive reserve, and genetic factors predisposing to cognitive dysfunction. These pathophysiological pathways may have synergistic effects that converge on dysfunction of the neurovascular unit and disruptions in functional connectivity leading to dementia post-ICH. Management of post-ICH dementia may include screening and monitoring, cognitive therapy, and pharmacotherapy. Non-invasive brain stimulation is an emerging therapeutic modality under investigation for safety and efficacy. Our review highlights that there remains a paucity of data and standardized reporting on incident dementia after spontaneous ICH. Further research is imperative for determining the incidence, risk factors, and pathophysiology of post-ICH dementia, in order to identify new therapies for the treatment of this debilitating condition.},
}

@article {pmid38640157,
year = {2024},
author = {Khaled, M and Al-Jamal, H and Tajer, L and El-Mir, R},
title = {Alzheimer's Disease in Lebanon: Exploring Genetic and Environmental Risk Factors-A Comprehensive Review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-231432},
pmid = {38640157},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that displays a high prevalence in Lebanon causing a local burden in healthcare and socio-economic sectors. Unfortunately, the lack of prevalence studies and clinical trials in Lebanon minimizes the improvement of AD patient health status. In this review, we include over 155 articles to cover the different aspects of AD ranging from mechanisms to possible treatment and management tools. We highlight some important modifiable and non-modifiable risk factors of the disease including genetics, age, cardiovascular diseases, smoking, etc. Finally, we propose a hypothetical genetic synergy model between APOE4 and TREM2 genes which constitutes a potential early diagnostic tool that helps in reducing the risk of AD based on preventative measures decades before cognitive decline. The studies on AD in Lebanon and the Middle East are scarce. This review points out the importance of genetic mapping in the understanding of disease pathology which is crucial for the emergence of novel diagnostic tools. Hence, we establish a rigid basis for further research to identify the most influential genetic and environmental risk factors for the purpose of using more specific diagnostic tools and possibly adopting a local management protocol.},
}

@article {pmid38639864,
year = {2024},
author = {Rahimi, A and Sameei, P and Mousavi, S and Ghaderi, K and Hassani, A and Hassani, S and Alipour, S},
title = {Application of CRISPR/Cas9 System in the Treatment of Alzheimer's Disease and Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {38639864},
issn = {1559-1182},
abstract = {Alzheimer's, Parkinson's, and Huntington's are some of the most common neurological disorders, which affect millions of people worldwide. Although there have been many treatments for these diseases, there are still no effective treatments to treat or completely stop these disorders. Perhaps the lack of proper treatment for these diseases can be related to various reasons, but the poor results related to recent clinical research also prompted doctors to look for new treatment approaches. In this regard, various researchers from all over the world have provided many new treatments, one of which is CRISPR/Cas9. Today, the CRISPR/Cas9 system is mostly used for genetic modifications in various species. In addition, by using the abilities available in the CRISPR/Cas9 system, researchers can either remove or modify DNA sequences, which in this way can establish a suitable and useful treatment method for the treatment of genetic diseases that have undergone mutations. We conducted a non-systematic review of articles and study results from various databases, including PubMed, Medline, Web of Science, and Scopus, in recent years. and have investigated new treatment methods in neurodegenerative diseases with a focus on Alzheimer's disease. Then, in the following sections, the treatment methods were classified into three groups: anti-tau, anti-amyloid, and anti-APOE regimens. Finally, we discussed various applications of the CRISPR/Cas-9 system in Alzheimer's disease. Today, using CRISPR/Cas-9 technology, scientists create Alzheimer's disease models that have a more realistic phenotype and reveal the processes of pathogenesis; following the screening of defective genes, they establish treatments for this disease.},
}

@article {pmid38638958,
year = {2024},
author = {Wu, J and Chen, J and Ge, Y and Huang, N and Luo, Y},
title = {Neuroprotective effect of tanshinone IIA-modified mesenchymal stem cells in a lipopolysaccharide-induced neuroinflammation model.},
journal = {Heliyon},
volume = {10},
number = {8},
pages = {e29424},
pmid = {38638958},
issn = {2405-8440},
abstract = {In this study, the neuroprotective potential of tanshinone IIA (TIIA)-modified mesenchymal stem cells (MSC) were investigated using a murine model of lipopolysaccharide (LPS)-induced neuroinflammation. The cognitive performance of the mice was assessed using the Y-maze and Morris water maze tests, while immunofluorescence and Western blot analyses were employed to evaluate the hippocampal expression of pertinent markers and inflammatory factors, respectively. The results from the behavioral experiments demonstrated discernible differences in learning and memory abilities between the model group and the control group (P < 0.05), confirming the successful induction of neuroinflammation. Both the MSC and TIIA-MSC groups exhibited enhancements in the cognitive abilities of neuroinflammatory mice, with the TIIA-MSC group demonstrating a more pronounced improvement (P < 0.01). Immunofluorescence analysis revealed significant activation of microglia in the model group, while the MSC and TIIA-MSC groups exhibited a reduction in hippocampal microglial activation, with the TIIA-MSC group displaying a more substantial decrease. A statistically significant difference in the expression levels of IL-1, IL-6, and TNF-α was observed between the model and control groups (P < 0.05), indicating that IL-1, IL-6, and TNF-α were downregulated in both the MSC and TIIA-MSC groups. Notably, the downregulatory effect was more prominent in the TIIA-MSC group (P < 0.01). Compared to MSC treatment alone, the administration of TIIA-modified MSC demonstrated a superior protective effect against lipopolysaccharide-induced neuroinflammation. These findings underscore the potential therapeutic efficacy of TIIA-modified MSC in mitigating neuroinflammatory responses.},
}

@article {pmid38638932,
year = {2024},
author = {Yan, F and Yang, M and Sun, Y and Tang, Q and Yuan, L},
title = {Case report: Methicillin-resistant Staphylococcus aureus with penicillin susceptible (PS-MRSA): first clinical report from a psychiatric hospital in China.},
journal = {Frontiers in medicine},
volume = {11},
number = {},
pages = {1380369},
pmid = {38638932},
issn = {2296-858X},
abstract = {This case report documents the first instance of Penicillin-Susceptible Methicillin-Resistant Staphylococcus aureus (PS-MRSA) in a Chinese psychiatric hospital. The strain was isolated from a patient with Alzheimer's disease who had a lower respiratory tract infection. Clinical and laboratory analyses, including mass spectrometry, antibiotic susceptibility testing, and whole-genome sequencing, confirmed the PS-MRSA strain. In this case, we systematically introduce the clinical symptoms, laboratory findings, and treatment responses associated with this PS-MRSA strain. This discovery offers a new perspective on our understanding of resistance mechanisms and expands our considerations for existing antibiotic treatments. It may fill a gap in the classification of MRSA strains, enhance the spectrum of MRSA resistance, and complete the therapeutic strategies for MRSA.},
}

@article {pmid38638303,
year = {2024},
author = {Jiang, S and Sydney, EJ and Runyan, AM and Serpe, R and Srikanth, M and Figueroa, HY and Yang, M and Myeku, N},
title = {5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1338502},
pmid = {38638303},
issn = {1662-5102},
abstract = {BACKGROUND: Accumulation of tau in synapses in the early stages of Alzheimer's disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of tau pathology through trans-synaptically connected neurons. Moreover, synaptic loss correlates with a decline in cognitive function, providing an opportunity to investigate therapeutic strategies to target synapses and synaptic tau to rescue or prevent cognitive decline in AD. One of the promising synaptic targets is the 5-HT4 serotonergic receptor present postsynaptically in the brain structures involved in the memory processes. 5-HT4R stimulation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tau pathology.

METHODS: The goal of this study was to investigate the impact of chronic stimulation of 5-HT4R by two agonists, prucalopride and RS-67333, in PS19 mice, a model of tauopathy. We utilized gradient assays to isolate pre- and post-synaptic compartments, followed by biochemical analyses for tau species and ubiquitinated proteins in the synaptic compartments and total brain tissue. Next, we performed kinetic assays to test the proteasome's hydrolysis capacity in treatment conditions. Moreover, behavioral tests such as the open field and non-maternal nest-building tests were used to evaluate anxiety-like behaviors and hippocampal-related cognitive functioning in the treatment paradigm.

RESULTS: Our results show that 5-HT4R agonism reduced tauopathy, reduced synaptic tau, increased proteasome activity, and improved cognitive functioning in PS19 mice. Our data suggest that enhanced proteasome activity by synaptic mediated signaling leads to the enhanced turnover of tau initially within synapses where the receptors are localized, and over time, the treatment attenuated the accumulation of tau aggregation and improved cognitive functioning of the PS19 mice.

CONCLUSION: Therefore, stimulation of 5-HT4R offers a promising therapy to rescue synapses from the accumulation of toxic synaptic tau, evident in the early stages of AD.},
}

@article {pmid38636309,
year = {2024},
author = {Durham, PG and Butnariu, A and Alghorazi, R and Pinton, G and Krishna, V and Dayton, PA},
title = {Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {21},
number = {3},
pages = {e00352},
doi = {10.1016/j.neurot.2024.e00352},
pmid = {38636309},
issn = {1878-7479},
abstract = {The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors. The review also addresses safety considerations, outlining the current understanding of potential risks and mitigation strategies associated with ultrasound exposure, including real-time monitoring and assessment of treatment efficacy. Among the large number of studies, significant successes are highlighted thus providing perspective on the future direction of the field.},
}

@article {pmid38634567,
year = {2024},
author = {Chai, B and Wu, Y and Yang, H and Fan, B and Cao, S and Zhang, X and Xie, Y and Hu, Z and Ma, Z and Zhang, Y and Pan, W and Meng, W and Meng, J and Tian, W and Zhang, J and Li, Y and Shao, Y and Wang, S},
title = {Tau Aggregation-Dependent Lipid Peroxide Accumulation Driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau Complex Inhibits Epithelial Ovarian Cancer Peritoneal Metastasis.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2310134},
doi = {10.1002/advs.202310134},
pmid = {38634567},
issn = {2198-3844},
support = {82260577//National Natural Science Foundation of China/ ; 82002726//National Natural Science Foundation of China/ ; 82203714//National Natural Science Foundation of China/ ; 82002758//National Natural Science Foundation of China/ ; H-2019007//Yunnan Provincial Medical Reserve Talents Project/ ; CZ0165//Young and Middle-aged Reserve Academic and Technical Leaders in Yunnan Province/ ; },
abstract = {Intraperitoneal dissemination is the main method of epithelial ovarian cancer (EOC) metastasis, which is related to poor prognosis and a high recurrence rate. Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures that are implicated in the regulation of tumor development. In this study, hsa_circ_0001546 is downregulated in EOC primary and metastatic tissues vs. control tissues and this phenotype has a favorable effect on EOC OS and DFS. hsa_circ_0001546 can directly bind with 14-3-3 proteins to act as a chaperone molecule and has a limited positive effect on 14-3-3 protein stability. This complex recruits CAMK2D to induce the Ser324 phosphorylation of Tau proteins, changing the phosphorylation status of Tau bound to 14-3-3 and ultimately forming the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex. The existence of this complex stimulates the production of Tau aggregation, which then induces the accumulation of lipid peroxides (LPOs) and causes LPO-dependent ferroptosis. In vivo, treatment with ferrostatin-1 and TRx0237 rescued the inhibitory effect of hsa_circ_0001546 on EOC cell spreading. Therefore, based on this results, ferroptosis caused by Tau aggregation occurs in EOC cells, which is not only in Alzheimer's disease- or Parkinson's disease-related cells and this kind of ferroptosis driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex is LPO-dependent rather than GPX4-dependent is hypothesized.},
}

@article {pmid38634361,
year = {2024},
author = {Andrade, SM and de Oliveira Marques, CC and de Lucena, LC and Vieira da Costa, K and de Souza, IC and da Silva Machado, CB and Queiroz, MEBS and Costa, LP and Silva, STD},
title = {Effect of transcranial direct current stimulation and transcranial magnetic stimulation on the cognitive function of individuals with Alzheimer's disease: a systematic review with meta-analysis and meta-regression.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/01616412.2024.2321779},
pmid = {38634361},
issn = {1743-1328},
abstract = {OBJECTIVE: To analyze the effects of transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) on the cognitive function of individuals with Alzheimer's disease (AD).

METHODS: This systematic review with meta-analysis and meta-regression included randomized clinical trials published until 05/2022. We included studies conducted with individuals with AD of both sexes, aged between 55 and 85 years, treated with tDCS, TMS, or both.

RESULTS: Twenty-one studies were included in the systematic review and sixteen in the meta-analysis. Meta-regression suggested a significant influence of anodic tDCS with current intensity of 1.5 mA on cognitive function. Significant results were found with treatment frequencies of three and five days a week for two weeks. Subgroup analysis found that anodic tDCS influences cognitive function, regardless of AD stage. Similar was observed for TMS using a frequency of 20 Hz and current intensity of 90% of the resting motor threshold.

DISCUSSION: Anodal tDCS and 20 Hz TMS have demonstrated the ability to improve cognitive function in AD by modulating neural activity. These therapies are safe and well-tolerated, offering promise as adjuncts to available pharmacological treatments. Studies with greater methodological rigor and parameter standardization are warranted. Comprehensive investigations involving neuroimaging techniques may provide a better understanding of the interaction between induced electrical fields and the complex neural networks affected in AD, paving the way for more personalized and effective neurostimulation approaches.},
}

@article {pmid38634273,
year = {2024},
author = {Akkaya, D and Seyhan, G and Sari, S and Barut, B},
title = {In vitro and in silico investigation of FDA-approved drugs to be repurposed against Alzheimer's disease.},
journal = {Drug development research},
volume = {85},
number = {3},
pages = {e22184},
doi = {10.1002/ddr.22184},
pmid = {38634273},
issn = {1098-2299},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Acetylcholinesterase/metabolism ; *Trimebutine/therapeutic use ; Cholinesterase Inhibitors/chemistry ; Models, Molecular ; Molecular Docking Simulation ; },
abstract = {Alzheimer's disease (AD), one of the main causes of dementia, is a neurodegenerative disorder. Cholinesterase inhibitors are used in the treatment of AD, but prolonged use of these drugs can lead to serious side effects. Drug repurposing is an approach that aims to reveal the effectiveness of drugs in different diseases beyond their clinical uses. In this work, we investigated in vitro and in silico inhibitory effects of 11 different drugs on cholinesterases. The results showed that trimebutine, theophylline, and levamisole had the highest acetylcholinesterase inhibitory actions among the tested drugs, and these drugs inhibited by 68.70 ± 0.46, 53.25 ± 3.40, and 44.03 ± 1.20%, respectively at 1000 µM. In addition, these drugs are bound to acetylcholinesterase via competitive manner. Molecular modeling predicted good fitness in acetylcholinesterase active site for these drugs and possible central nervous system action for trimebutine. All of these results demonstrated that trimebutine was determined to be the drug with the highest potential for use in AD.},
}

Humans
*Alzheimer Disease/drug therapy
Acetylcholinesterase/metabolism
*Trimebutine/therapeutic use
Cholinesterase Inhibitors/chemistry
Models, Molecular
Molecular Docking Simulation

@article {pmid38632621,
year = {2024},
author = {Liu, J and Wu, H and Robertson, DH and Zhang, J},
title = {Text mining and portal development for gene-specific publications on Alzheimer's disease and other neurodegenerative diseases.},
journal = {BMC medical informatics and decision making},
volume = {24},
number = {Suppl 3},
pages = {98},
pmid = {38632621},
issn = {1472-6947},
support = {U54 AG065181/AG/NIA NIH HHS/United States ; 5U54AG065181-02/NH/NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Alzheimer Disease ; *Neurodegenerative Diseases ; Data Mining/methods ; PubMed ; Databases, Factual ; },
abstract = {BACKGROUND: Tremendous research efforts have been made in the Alzheimer's disease (AD) field to understand the disease etiology, progression and discover treatments for AD. Many mechanistic hypotheses, therapeutic targets and treatment strategies have been proposed in the last few decades. Reviewing previous work and staying current on this ever-growing body of AD publications is an essential yet difficult task for AD researchers.

METHODS: In this study, we designed and implemented a natural language processing (NLP) pipeline to extract gene-specific neurodegenerative disease (ND) -focused information from the PubMed database. The collected publication information was filtered and cleaned to construct AD-related gene-specific publication profiles. Six categories of AD-related information are extracted from the processed publication data: publication trend by year, dementia type occurrence, brain region occurrence, mouse model information, keywords occurrence, and co-occurring genes. A user-friendly web portal is then developed using Django framework to provide gene query functions and data visualizations for the generalized and summarized publication information.

RESULTS: By implementing the NLP pipeline, we extracted gene-specific ND-related publication information from the abstracts of the publications in the PubMed database. The results are summarized and visualized through an interactive web query portal. Multiple visualization windows display the ND publication trends, mouse models used, dementia types, involved brain regions, keywords to major AD-related biological processes, and co-occurring genes. Direct links to PubMed sites are provided for all recorded publications on the query result page of the web portal.

CONCLUSION: The resulting portal is a valuable tool and data source for quick querying and displaying AD publications tailored to users' interested research areas and gene targets, which is especially convenient for users without informatic mining skills. Our study will not only keep AD field researchers updated with the progress of AD research, assist them in conducting preliminary examinations efficiently, but also offers additional support for hypothesis generation and validation which will contribute significantly to the communication, dissemination, and progress of AD research.},
}

Animals
Mice
*Alzheimer Disease
*Neurodegenerative Diseases
Data Mining/methods
PubMed
Databases, Factual

@article {pmid38631571,
year = {2024},
author = {Yang, J and Liao, Y and Cao, C and Yu, Q and Zhang, D and Yan, C},
title = {Structural identification and anti-neuroinflammatory effects of a pectin-arabinoglucuronogalactan complex, AOPB-1-1, isolated from Asparagus officinalis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {131593},
doi = {10.1016/j.ijbiomac.2024.131593},
pmid = {38631571},
issn = {1879-0003},
abstract = {Asparagus officinalis L. is a horticultural crop that contains a variety of bioactive compounds with anti-inflammatory effects. Aqueous extracts of A. officinalis can noticeably improve the learning and memory function of model mice. Herein, a pectin-arabinoglucuronogalactan complex (AOPB-1-1) with a relative molecular weight of 90.8 kDa was isolated from A. officinalis. The repeating structural unit of AOPB-1-1 was identified through monosaccharide composition, methylation analysis, uronic acid reduction, partial acid hydrolysis, and nuclear magnetic resonance spectroscopy. AOPB-1-1 contains the rhamnogalacturonan-I (RG-I) domain of pectin polysaccharides (PPs) and arabinoglucuronogalactan (AGG) regions. The backbone of the AGG region is composed of →3,6)-β-D-Galp-(1 → and →4)-β-D-Glcp-(1 → residues substituted at the 4-position to the →4)-α-D-GalAp-(1 → residues of the RG-I main chain. The anti-neuroinflammatory activity of AOPB-1-1 suggests that it can significantly reduce the content of inflammatory cytokines, including nitric oxide, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) and inhibit the expression of inflammatory genes including cyclooxygenase-2, nitric oxide synthase, TNF-α, IL-6, and interleukin-1β in LPS-stimulated BV2 cells. Furthermore, its inhibitory effects on TNF-α and IL-6 levels were even better than those of minocycline. The significant anti-neuroinflammatory activity of AOPB-1-1 suggests its applicability as a therapeutic option for the treatment of Alzheimer's disease.},
}

@article {pmid38630416,
year = {2024},
author = {Furneri, G and Varrasi, S and Guerrera, CS and Platania, GA and Torre, V and Boccaccio, FM and Testa, MF and Martelli, F and Privitera, A and Razza, G and Santagati, M and Di Nuovo, S and Pirrone, C and Castellano, S and Caraci, F and Monastero, R},
title = {Combining Mini-Mental State Examination and Montreal Cognitive Assessment for assessing the clinical efficacy of cholinesterase inhibitors in mild Alzheimer's disease: a pilot study.},
journal = {Aging clinical and experimental research},
volume = {36},
number = {1},
pages = {95},
pmid = {38630416},
issn = {1720-8319},
mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use ; Pilot Projects ; *Alzheimer Disease/drug therapy ; Mental Status and Dementia Tests ; Treatment Outcome ; },
abstract = {Current drugs for Alzheimer's Disease (AD), such as cholinesterase inhibitors (ChEIs), exert only symptomatic activity. Different psychometric tools are needed to assess cognitive and non-cognitive dimensions during pharmacological treatment. In this pilot study, we monitored 33 mild-AD patients treated with ChEIs. Specifically, we evaluated the effects of 6 months (Group 1 = 17 patients) and 9 months (Group 2 = 16 patients) of ChEIs administration on cognition with the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Frontal Assessment Battery (FAB), while depressive symptoms were measured with the Hamilton Depression Rating Scale (HDRS). After 6 months (Group 1), a significant decrease in MoCA performance was detected. After 9 months (Group 2), a significant decrease in MMSE, MoCA, and FAB performance was observed. ChEIs did not modify depressive symptoms. Overall, our data suggest MoCA is a potentially useful tool for evaluating the effectiveness of ChEIs.},
}

Humans
*Cholinesterase Inhibitors/therapeutic use
Pilot Projects
*Alzheimer Disease/drug therapy
Mental Status and Dementia Tests
Treatment Outcome

@article {pmid38630202,
year = {2024},
author = {Dai, M and Guo, Z and Xia, H and Zhu, H and Li, J and Hou, H and Zhao, G and Liu, X},
title = {Predicting the efficacy of donepezil intervention in Alzheimer's disease patients using regional homogeneity in the inferior orbitofrontal cortex.},
journal = {Aging clinical and experimental research},
volume = {36},
number = {1},
pages = {94},
pmid = {38630202},
issn = {1720-8319},
support = {2017KY109//by the General Project of the Department of Science and Technology of Zhejiang Province/ ; },
mesh = {Humans ; Donepezil/therapeutic use ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Prefrontal Cortex/diagnostic imaging ; Brain ; Cognition ; },
abstract = {BACKGROUND: Although donepezil is a commonly used drug for treating Alzheimer's disease (AD), the mechanisms by which it affects patients' functional brain activity, and thus modulates clinical symptoms, remain unclear.

METHODS: In the present study, we used resting-state functional magnetic resonance imaging (MRI) and regional homogeneity (ReHo) to investigate the effects of donepezil on local brain activity in AD patients. Resting-state functional MRI data were collected from 32 subjects: 16 healthy controls and 16 AD patients. All 16 AD patients underwent 6 months of donepezil treatment and received two MRI scans (pre- and post-intervention). Analysis of covariance and post hoc analyses were used to compare ReHo differences among the healthy controls, pre-intervention AD patients, and post-intervention AD patients. Pearson correlation analysis was used to examine relationships between ReHo values in differential brain regions and clinical symptoms.

RESULTS: Compared with healthy controls, post-intervention AD patients had reduced ReHo in the orbital part of the inferior frontal gyrus, and pre-intervention AD patients had reduced ReHo in the orbital part of the right inferior frontal gyrus. Pattern recognition models revealed that pre-intervention ReHo values in abnormal brain regions of AD patients were 76% accurate for predicting the efficacy of donepezil on cognitive function and 65% accurate for predicting its efficacy on depressive symptoms.

CONCLUSIONS: These findings deepen our understanding of the brain mechanisms underlying the clinical efficacy of donepezil in AD patients, and provide a novel way to predict its clinical efficacy in such patients.},
}

Humans
Donepezil/therapeutic use
*Alzheimer Disease/diagnostic imaging/drug therapy
Prefrontal Cortex/diagnostic imaging
Brain
Cognition

@article {pmid38630163,
year = {2024},
author = {Perneczky, R and , and Nitschmann, S},
title = {[The monoclonal antibody gantenerumab in the treatment of early Alzheimer's disease].},
journal = {Innere Medizin (Heidelberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {38630163},
issn = {2731-7099},
}

@article {pmid38630150,
year = {2024},
author = {Yun, Q and Ma, SF and Zhang, WN and Gu, M and Wang, J},
title = {FoxG1 as a Potential Therapeutic Target for Alzheimer's Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway.},
journal = {Cellular and molecular neurobiology},
volume = {44},
number = {1},
pages = {35},
pmid = {38630150},
issn = {1573-6830},
support = {CJ20230082//Applied Basic Research Project of Changzhou/ ; xz202204//Station level project of Changzhou Blood Center/ ; BE2022782//Clinic Development Fund of Jiangsu Province/ ; },
mesh = {Animals ; Mice ; *Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; *Alzheimer Disease ; AMP-Activated Protein Kinases ; Neuroinflammatory Diseases ; Autophagy ; RNA, Small Interfering ; },
abstract = {An increasing body of research suggests that promoting microglial autophagy hinders the neuroinflammation initiated though the NLRP3 inflammasome activation in Alzheimer's disease (AD). The function of FoxG1, a crucial transcription factor involved in cell survival by regulating mitochondrial function, remains unknown during the AD process and neuroinflammation occurs. In the present study, we firstly found that Aβ peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aβ25-35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aβ25-35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aβ25-35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aβ25-35 stimulation, we employed siRNA to decrease the expression of FoxG1 in N2A cells. A substantial reduction in autophagy level (Beclin1, LC3II, SQSTM1/P62) and a notable growth in inflammatory response (NLRP3, TNF-α, and IL-6) were observed. In addition, we found FoxG1 overexpression owned the effect on the activation of AMPK/mTOR autophagy pathway and siRNA-FoxG1 successfully abolished this effect. Lastly, FoxG1 suppressed the NLRP3 inflammasome and enhanced the cognitive function in AD-like mouse model induced by Aβ25-35. Confirmed by cellular and animal experiments, FoxG1 suppressed NLRP3-mediated neuroinflammation, which was strongly linked to autophagy regulated by AMPK/mTOR. Taken together, FoxG1 may be a critical node in the pathologic progression of AD and has the potential to serve as therapeutic target.},
}

Animals
Mice
*Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
*Alzheimer Disease
AMP-Activated Protein Kinases
Neuroinflammatory Diseases
Autophagy
RNA, Small Interfering

@article {pmid38633542,
year = {2022},
author = {Akgül, F and Sevim, B and Arslan, Y and Şencan, M and Atabey, P and Aktaş, A},
title = {Predictors of Severity and Mortality in COVID-19: A Retrospective Study from Batman, Turkey.},
journal = {Infectious diseases & clinical microbiology},
volume = {4},
number = {1},
pages = {18-29},
pmid = {38633542},
issn = {2667-646X},
abstract = {OBJECTIVE: It is increasingly important to identify risk factors for COVID-19-associated mortality to provide access to early treatment. This study aimed to investigate the relationship between COVID-19 severity and laboratory data and demographic characteristics of hospitalized patients and to identify factors predicting mortality in COVID-19.

MATERIALS AND METHODS: The study is a retrospective and single-center study. Data of 1298 COVID-19 patients confirmed by a positive real-time polymerase chain reaction test for COVID-19 and treated at the hospital were retrospectively analyzed. Study patients were divided into three groups based on the clinical severity of disease: the mild-moderate group (n:954) and the severe (n:310) and critical (n:34) groups. Demographic characteristics, underlying diseases, and laboratory findings were compared between groups.

RESULTS: Multivariate logistic and ordinal logistic regression analysis revealed that male gender, old age, diabetes mellitus, coronary artery disease, cerebrovascular event, malignancy, chronic obstructive pulmonary disease, chronic renal failure, chronic hepatitis B, and Alzheimer's disease/dementia/Parkinson's disease (among neurological diseases) were independently associated with and significantly increased the development of severe disease and mortality.

CONCLUSION: The COVID-19 pandemic continues to be a significant health problem affecting all of humanity. Determining risk factors for COVID-19 severity and mortality are critical for classifying critical cases at the time of initial diagnosis, establishing appropriately specific treatment protocols, and ensuring access to early treatment.},
}

@article {pmid38629411,
year = {2024},
author = {Wirth, S and Schlößer, A and Beiersdorfer, A and Schweizer, M and Woo, MS and Friese, MA and Lohr, C and Grochowska, KM},
title = {Astrocytic uptake of posttranslationally modified amyloid-β leads to endolysosomal system disruption and induction of pro-inflammatory signaling.},
journal = {Glia},
volume = {},
number = {},
pages = {},
doi = {10.1002/glia.24539},
pmid = {38629411},
issn = {1098-1136},
support = {CRC 1436 TPA02//Deutsche Forschungsgemeinschaft/ ; SFB 1328 project number 335447717//Deutsche Forschungsgemeinschaft/ ; DE-20057p//Alzheimer Forschung Initiative/ ; },
abstract = {The disruption of astrocytic catabolic processes contributes to the impairment of amyloid-β (Aβ) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late-onset Alzheimer's disease (AD). While it is known that the posttranslational modifications of Aβ have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N-terminally pyroglutamylated Aβ3(pE)-42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro-inflammatory cytokine tumor necrosis factor α and synapse loss. Here we report that Aβ3(pE)-42, but not Aβ1-42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing the formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics, lysosome-dependent calcium signaling, and upregulates the lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with a lysosomal protease inhibitor, E-64, rescues GFAP upregulation, NF-κB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro-inflammatory signaling and related synapse loss. Collectively, our data suggest that Aβ3(pE)-42-induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro-inflammatory signaling and synapse loss, hallmarks of AD-pathology.},
}

@article {pmid38629395,
year = {2024},
author = {Liu, Y and Li, X and Liu, S and Liang, T and Wu, Y and Wang, X and Li, Y and Xu, Y},
title = {Study on Gamma sensory flicker for Insomnia.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/00207454.2024.2342974},
pmid = {38629395},
issn = {1563-5279},
abstract = {OBJECTIVES: Insomnia has been the subject of much systematic research because it is a risk factor for a variety of diseases. There is some evidence that gamma sensory stimulation therapy has also been demonstrated to improve sleep quality for people with Alzheimer's disease. However, it is unclear whether this method is effective for treating insomnia. The principal objective of this project was to investigate the efficacy and safety of gamma sensory flicker in improving the sleep quality of insomnia patients.

METHODS: Thirty-seven participants with insomnia were recruited for this prospective observational study. For a duration of 8 weeks, participants were exposed to flicker stimulation through a light and sound device.

RESULTS: During the main phase of the study, adherence rates averaged 92.21%. Additionally, no severe adverse events were reported for flicker treatment. Analysis of sleep diaries indicated that 40 Hz flickers can enhance sleep quality by reducing sleep onset latencies, and arousals, and increasing total sleep duration.

CONCLUSIONS: Gamma sensory flicker improves sleep quality in people suffering from insomnia.},
}

@article {pmid38628727,
year = {2024},
author = {Zou, C and Yang, T and Huang, X and Ren, X and Yang, C and Xu, B and Liu, J},
title = {Inhibition of autophagosome-lysosome fusion contributes to TDCIPP-induced Aβ1-42 production in N2a-APPswe cells.},
journal = {Heliyon},
volume = {10},
number = {8},
pages = {e26832},
pmid = {38628727},
issn = {2405-8440},
abstract = {Alzheimer's disease is the most common form of dementia and is characterized by cognitive impairment. The disruption of autophagosome-lysosome function has been linked to the pathogenesis of Alzheimer's disease. Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphorus flame retardant that has the potential to cause neuronal damage. We found that TDCIPP significantly increased the expression of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), presenilin-1 (PS1) and Aβ42. Proteomic studies with TMT labeling revealed changes in the profiles of N2a-APPswe cells after exposure to TDCIPP. Proteomic and bioinformatics analyses revealed that lysosomal proteins were dysregulated in N2a-APPswe cells after treatment with TDCIPP. The LC3, P62, CTSD, and LAMP1 levels were increased after TDCIPP exposure, and dysregulated protein expression was validated by Western blotting. The exposure to TDCIPP led to the accumulation of autophagosomes, and this phenomenon was enhanced in the presence of chloroquine (CQ). Our results revealed for the first time that TDCIPP could be a potential environmental risk factor for AD development. The inhibition of autophagosome-lysosome fusion may have a significant impact on the generation of Aβ1-42 in response to TDCIPP.},
}

@article {pmid38628697,
year = {2024},
author = {Wang, H and Shi, L and Luo, S and Luo, Y and Xu, C and Qiu, G and Guo, Q and Chen, C and Lu, T and Liu, K and Zhu, F},
title = {Associations of apolipoprotein E ε4 allele, regional cerebral blood flow, and serum liver function markers in patients with cognitive impairment.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1345705},
pmid = {38628697},
issn = {1664-2295},
abstract = {INTRODUCTION: The ε4 allele of the apolipoprotein E gene (APOE4) is expressed abundantly in both the brain and peripheral circulation as a genetic risk factor for Alzheimer's disease (AD). Cerebral blood flow (CBF) dysfunction is an essential feature of AD, and the liver plays an important role in the pathogenesis of dementia. However, the associations of APOE4 with CBF and liver function markers in patients with cognitive impairment remains unclear. We aimed to evaluate the associations of APOE4 with CBF measured by arterial spin labeling (ASL) magnetic resonance imaging (MRI) and serum liver function markers in participants who were diagnosed with cognitive impairment.

METHODS: Fourteen participants with AD and sixteen with amnestic mild cognitive impairment (MCI) were recruited. In addition to providing comprehensive clinical information, all patients underwent laboratory tests and MRI. All participants were divided into carriers and noncarriers of the ε4 allele, and T-tests and Mann-Whitney U tests were used to observe the differences between APOE4 carriers and noncarriers in CBF and liver function markers.

RESULTS: Regarding regional cerebral blood flow (rCBF), APOE4 carriers showed hyperperfusion in the bilateral occipital cortex, bilateral thalamus, and left precuneus and hypoperfusion in the right lateral temporal cortex when compared with noncarriers. Regarding serum liver function markers, bilirubin levels (including total, direct, and indirect) were lower in APOE4 carriers than in noncarriers.

CONCLUSION: APOE4 exerts a strong effect on CBF dysfunction by inheritance, representing a risk factor for AD. APOE4 may be related to bilirubin metabolism, potentially providing specific neural targets for the diagnosis and treatment of AD.},
}

@article {pmid38628595,
year = {2024},
author = {Qiu, C and Li, Z and Leigh, DA and Duan, B and Stucky, JE and Kim, N and Xie, G and Lu, KP and Zhou, XZ},
title = {The role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.},
journal = {Frontiers in cell and developmental biology},
volume = {12},
number = {},
pages = {1343962},
pmid = {38628595},
issn = {2296-634X},
abstract = {Tauopathies are neurodegenerative diseases characterized by deposits of abnormal Tau protein in the brain. Conventional tauopathies are often defined by a limited number of Tau epitopes, notably neurofibrillary tangles, but emerging evidence suggests structural heterogeneity among tauopathies. The prolyl isomerase Pin1 isomerizes cis P-tau to inhibit the development of oligomers, tangles and neurodegeneration in multiple neurodegenerative diseases such as Alzheimer's disease, traumatic brain injury, vascular contribution to cognitive impairment and dementia (VCID) and preeclampsia (PE). Thus, cis P-tau has emerged as an early etiological driver, blood marker and therapeutic target for multiple neurodegenerative diseases, with clinical trials ongoing. The discovery of cis P-tau and other tau pathologies in VCID and PE calls attention for simplistic classification of tauopathy in neurodegenerative diseases. These recent advances have revealed the exciting novel role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.},
}

@article {pmid38627829,
year = {2024},
author = {Luo, YX and Yang, LL and Yao, XQ},
title = {Gut microbiota-host lipid crosstalk in Alzheimer's disease: implications for disease progression and therapeutics.},
journal = {Molecular neurodegeneration},
volume = {19},
number = {1},
pages = {35},
pmid = {38627829},
issn = {1750-1326},
support = {No.82371427//National Natural Science Foundation of China/ ; CSTB2023NSCQBHX0018//Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission/ ; CSTB2023NSCQ-MSX0323//Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission/ ; No. kryc-lj-2105//Chongqing Medical University/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Gastrointestinal Microbiome/physiology ; Lipid Metabolism ; Disease Progression ; Lipids ; },
abstract = {Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively contribute to the progression of Alzheimer's disease. The role of gut microbiota in Alzheimer's disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer's disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer's disease based on existing data.},
}

Humans
*Alzheimer Disease/metabolism
*Gastrointestinal Microbiome/physiology
Lipid Metabolism
Disease Progression
Lipids

@article {pmid38626288,
year = {2024},
author = {Borikar, SP and Sonawane, DS and Tapre, DN and Jain, SP},
title = {Exploring the neuropharmacological potential of empagliflozin on nootropic and scopolamine-induced amnesic model of Alzheimer's like conditions in rats.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/00207454.2024.2342973},
pmid = {38626288},
issn = {1563-5279},
abstract = {Alzheimer disease (AD) is one of the most challenging and prevalent neurodegenerative disorder globally with a rising prevalence, characterized by progressive cognitive decline, memory loss, and behavioural changes. Current research aims to determine the nootropic and anti-amnesic effect of Empagliflozin (EMPA) against scopolamine-induced amnesia in rats, by modulating the cholinergic and N-Methyl D-Aspartate (NMDA) receptors. Rats were treated once daily with an EMPA (5 and 10 mg/kg) and donepezil (2.5 mg/kg) for successive 26 days. During the final 13 days of treatment, a daily injection of scopolamine (1 mg/kg) was administered to induce cognitive deficits. EMPA was found to be significantly reduce escape latency, increase time spent in the target quadrant, and enhanced the number of target zone crossings in the Morris water maze (MWM) test, indicating improved spatial memory. Moreover, EMPA increased the recognition index and the number of spontaneous alternations in the novel object recognition (NOR) and Y-maze tests, respectively, suggesting enhanced memory. Additionally, doses of EMPA (5 mg/kg, 10 mg/kg) exhibited memory-enhancing effects even in the absence of scopolamine-induced impairment. Biochemical analysis revealed that EMPA elevated the levels of glutathione (GSH), a potent antioxidant, while decreasing lipid peroxidation (LPO) activity and increasing catalase (CAT) levels, indicating its antioxidative properties. Interestingly molecular docking studies revealed that EMPA fit perfectly in the active sites of M1 muscarinic acetylcholine (mACh) and NMDA receptors. These results indicated that the nootropic and antiamnesic effect of EMPA is medicated via M1 and NMDA receptors and might be a pertinent solution for the AD.},
}

@article {pmid38625863,
year = {2024},
author = {Lee, C and Friedman, A},
title = {Generating PET scan patterns in Alzheimer's by a mathematical model.},
journal = {PloS one},
volume = {19},
number = {4},
pages = {e0299637},
pmid = {38625863},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/pathology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; Models, Theoretical ; },
abstract = {Alzheimer disease (AD) is the most common form of dementia. The cause of the disease is unknown, and it has no cure. Symptoms include cognitive decline, memory loss, and impairment of daily functioning. The pathological hallmarks of the disease are aggregation of plaques of amyloid-β (Aβ) and neurofibrillary tangles of tau proteins (τ), which can be detected in PET scans of the brain. The disease can remain asymptomatic for decades, while the densities of Aβ and τ continue to grow. Inflammation is considered an early event that drives the disease. In this paper, we develop a mathematical model that can produce simulated patterns of (Aβ,τ) seen in PET scans of AD patients. The model is based on the assumption that early inflammations, R and [Formula: see text], drive the growth of Aβ and τ, respectively. Recently approved drugs can slow the progression of AD in patients, provided treatment begins early, before significant damage to the brain has occurred. In line with current longitudinal studies, we used the model to demonstrate how to assess the efficacy of such drugs when given years before the disease becomes symptomatic.},
}

Humans
*Alzheimer Disease/pathology
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
Models, Theoretical

@article {pmid38625441,
year = {2024},
author = {Besin, V and Humardani, FM and Yulianti, T and Putra, SED and Triana, R and Justyn, M},
title = {The Apo gene's genetic variants: hidden role in Asian vascular risk.},
journal = {Neurogenetics},
volume = {},
number = {},
pages = {},
pmid = {38625441},
issn = {1364-6753},
abstract = {Vascular risk factors, including diabetes, hypertension, hyperlipidemia, and obesity, pose significant health threats with implications extending to neuropsychiatric disorders such as stroke and Alzheimer's disease. The Asian population, in particular, appears to be disproportionately affected due to unique genetic predispositions, as well as epigenetic factors such as dietary patterns and lifestyle habits. Existing management strategies often fall short of addressing these specific needs, leading to greater challenges in prevention and treatment. This review highlights a significant gap in our understanding of the impact of genetic screening in the early detection and tailored treatment of vascular risk factors among the Asian population. Apolipoprotein, a key player in cholesterol metabolism, is primarily associated with dyslipidemia, yet emerging evidence suggests its involvement in conditions such as diabetes, hypertension, and obesity. While genetic variants of vascular risk are ethnic-dependent, current evidence indicates that epigenetics also exhibits ethnic specificity. Understanding the interplay between Apolipoprotein and genetics, particularly within diverse ethnic backgrounds, has the potential to refine risk stratification and enhance precision in management. For Caucasian carrying the APOA5 rs662799 C variant, pharmacological interventions are recommended, as dietary interventions may not be sufficient. In contrast, for Asian populations with the same genetic variant, dietary modifications are initially advised. Should dyslipidemia persist, the consideration of pharmaceutical agents such as statins is recommended.},
}

@article {pmid38625027,
year = {2024},
author = {Zhou, AL and Swaminathan, SK and Salian, VS and Wang, L and Curran, GL and Min, HK and Lowe, VJ and Kandimalla, KK},
title = {Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood-Brain Barrier.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.3c00784},
pmid = {38625027},
issn = {1543-8392},
abstract = {The blood-brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-β (Aβ) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer's disease (AD) brain, increased Aβ levels are paralleled by decreased insulin levels, which are accompanied by insulin signaling deficits at the BBB. Thus, we investigated the impact of insulin-like growth factor and insulin receptor (IGF1R and IR) signaling on Aβ and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of [125]I radiolabeled Aβ peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [[125]I]iodo-Aβ42 decreased upon AG1024 treatment. Additionally, the brain influx of [[125]I]iodoinsulin, [[125]I]iodo-Aβ42, [[125]I]iodo-Aβ40, and [[125]I]iodo-BSA (BBB integrity marker) was decreased, increased, unchanged, and unchanged, respectively, upon AG1024 treatment. Subsequent mechanistic studies were performed using an in vitro BBB cell model. The cell uptake of [[125]I]iodoinsulin, [[125]I]iodo-Aβ42, and [[125]I]iodo-Aβ40 was decreased, increased, and unchanged, respectively, upon AG1024 treatment. Further, AG1024 reduced the phosphorylation of insulin signaling kinases (Akt and Erk) and the membrane expression of Aβ and insulin trafficking receptors (LRP-1 and IR-β). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aβ peptides and insulin. Moreover, deficits in IGF1R and IR signaling, as observed in the brains of type II diabetes and AD patients, are expected to increase Aβ accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.},
}

@article {pmid38623983,
year = {2024},
author = {Sen, D and Rathee, S and Pandey, V and Jain, SK and Patil, UK},
title = {Comprehensive Insights into Pathophysiology of Alzheimer's Disease: Herbal Approaches for Mitigating Neurodegeneration.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050309057240404075003},
pmid = {38623983},
issn = {1875-5828},
abstract = {Alzheimer's disease [AD] is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and functional impairment. Despite extensive research, the exact etiology remains elusive. This review explores the multifaceted pathophysiology of AD, focusing on key hypotheses such as the cholinergic hypothesis, hyperphosphorylated Tau Protein and Amyloid β hypothesis, oxidative stress hypothesis, and the metal ion hypothesis. Understanding these mechanisms is crucial for developing effective therapeutic strategies. Current treatment options for AD have limitations, prompting the exploration of alternative approaches, including herbal interventions. Cholinesterase inhibitors, targeting the cholinergic hypothesis, have shown modest efficacy in managing symptoms. Blocking Amyloid β [Aβ] and targeting hyperphosphorylated tau protein are under investigation, with limited success in clinical trials. Oxidative stress, implicated in AD pathology, has led to the investigation of antioxidants. Natural products, such as Punica granatum Linn, Radix Scutellariae, and Curcuma longa have demonstrated antioxidant properties, along with anti-inflammatory effects, offering potential neuroprotective benefits. Several herbal extracts, including Ginkgo biloba, Bacopa monnieri, and Withania somnifera, have shown promise in preclinical studies. Compounds like Huperzine A, Melatonin, and Bryostatin exhibit neuroprotective effects through various mechanisms, including cholinergic modulation and anti-inflammatory properties. However, the use of herbal drugs for AD management faces limitations, including standardization issues, variable bioavailability, and potential interactions with conventional medications. Additionally, the efficacy and safety of many herbal products remain to be established through rigorous clinical trials. This review also highlights promising natural products currently in clinical trials, such as Resveratrol and Homotaurine, and their potential impact on AD progression. DHA, an omega-3 fatty acid, has shown cognitive benefits, while Nicotine is being explored for its neuroprotective effects. In conclusion, a comprehensive understanding of the complex pathophysiology of AD and the exploration of herbal interventions offer a holistic approach to managing this devastating disease. Future research should address the limitations associated with herbal drugs and further evaluate the efficacy of promising natural products in clinical settings.},
}

@article {pmid38623856,
year = {2024},
author = {Kovalová, M and Gottfriedová, N and Mrázková, E and Janout, V and Janoutová, J},
title = {Cognitive impairment, neurodegenerative disorders, and olfactory impairment: A literature review.},
journal = {Otolaryngologia polska = The Polish otolaryngology},
volume = {78},
number = {2},
pages = {1-17},
doi = {10.5604/01.3001.0053.6158},
pmid = {38623856},
issn = {2300-8423},
mesh = {Humans ; *Cognitive Dysfunction/complications/diagnosis/psychology ; *Alzheimer Disease/complications/diagnosis/psychology ; *Olfaction Disorders/diagnosis/etiology ; Smell ; },
abstract = {
Introduction: The early detection and diagnosis of dementia are of key importance in treatment, slowing disease progression, or suppressing symptoms. The possible role of changes in the sense of smell is considered with regard to potential markers for early detection of Alzheimer's disease (AD).

Materials and methods: A literature search was conducted using the electronic databases PubMed, Scopus, and Web of Science between May 30, 2022 and August 2, 2022. The term "dementia" was searched with keyword combinations related to olfaction.

Results: A total of 1,288 records were identified through the database search. Of these articles, 49 were ultimately included in the analysis. The results showed the potential role of changes in the sense of smell as potential biomarkers for early detection of AD. Multiple studies have shown that olfactory impairment may be observed in patients with AD, PD, MCI, or other types of dementia. Even though smell tests are able to detect olfactory loss caused by neurodegenerative diseases, they cannot reliably distinguish between certain diseases.

Conclusions: In individuals with cognitive impairment or neurodegenerative diseases, olfactory assessment has repeatedly been reported to be used for early diagnosis, but not for differential diagnosis. }

Humans
*Cognitive Dysfunction/complications/diagnosis/psychology
*Alzheimer Disease/complications/diagnosis/psychology
*Olfaction Disorders/diagnosis/etiology
Smell

@article {pmid38623574,
year = {2024},
author = {Li, L and Huang, Z and Wu, M and Li, X and Xiao, B and Yao, D and Mo, B},
title = {Trehalose improves the movement ability of AβarcDrosophila by restoring the damaged mitochondria.},
journal = {Translational neuroscience},
volume = {15},
number = {1},
pages = {20220338},
doi = {10.1515/tnsci-2022-0338},
pmid = {38623574},
issn = {2081-3856},
abstract = {BACKGROUND: The deposition of Aβ42 has been regarded as one of the important pathological features of Alzheimer's disease (AD). However, drug development for Aβ42 toxicity has been progressed slowly.

OBJECTIVE: Our aim was to introduce the effect and related mechanism of trehalose on an Aβarc (arctic mutant Aβ42) Drosophila AD model.

METHODS: The human Aβarc was expressed in Drosophila to construct the AD model. Trehalose was added to the culture vial. The movement ability was determined by detecting climbing ability and flight ability. Enzyme-linked immunosorbent assay was used to detect the levels of Aβarc, ATP, and lactate. Electron microscopy assay, mitochondrial membrane potential assay, and mitochondrial respiration assay were used to assess the mitochondrial structure and function.

RESULTS: Trehalose strongly improved the movement ability of Aβarc Drosophila in a concentration gradient-dependent manner. Furthermore, trehalose increased the content of ATP and decreased the content of Aβarc and lactate both in the brain and thorax of Aβarc Drosophila. More importantly, the mitochondrial structure and function were greatly improved by trehalose treatment in Aβarc Drosophila.

CONCLUSION: Trehalose improves movement ability at least partly by reducing the Aβarc level and restoring the mitochondrial structure and function in Aβarc Drosophila.},
}

@article {pmid38623385,
year = {2024},
author = {Crump, C and Sieh, W and Vickrey, BG and Edwards, AC and Sundquist, J and Sundquist, K},
title = {Risk of depression in persons with Alzheimer's disease: A national cohort study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12584},
pmid = {38623385},
issn = {2352-8729},
support = {R03 AG083596/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Depression is a risk factor and possible prodromal symptom of Alzheimer's disease (AD), but little is known about subsequent risk of developing depression in persons with AD.

METHODS: National matched cohort study was conducted of all 129,410 persons diagnosed with AD and 390,088 with all-cause dementia during 1998-2017 in Sweden, and 3,900,880 age- and sex-matched controls without dementia, who had no prior depression. Cox regression was used to compute hazard ratios (HRs) for major depression through 2018.

RESULTS: Cumulative incidence of major depression was 13% in persons with AD and 3% in controls. Adjusting for sociodemographic factors and comorbidities, risk of major depression was greater than two-fold higher in women with AD (HR, 2.21; 95% confidence interval [CI], 2.11-2.32) or men with AD (2.68; 2.52-2.85), compared with controls. Similar results were found for all-cause dementia.

DISCUSSION: Persons diagnosed with AD or related dementias need close follow-up for timely detection and treatment of depression.

HIGHLIGHTS: In a large cohort, women and men with AD had >2-fold subsequent risk of depression.Risks were highest in the first year (>3-fold) but remained elevated ≥3 years later.Risk of depression was highest in persons aged ≥85 years at AD diagnosis.Persons with AD need close follow-up for detection and treatment of depression.},
}

@article {pmid38623384,
year = {2024},
author = {Schworer, EK and Handen, BL and Petersen, M and O'Bryant, S and Peven, JC and Tudorascu, DL and Lee, L and Krinsky-McHale, SJ and Hom, CL and Clare, ICH and Christian, BT and Schupf, N and Lee, JH and Head, E and Mapstone, M and Lott, I and Ances, BM and Zaman, S and Brickman, AM and Lai, F and Rosas, HD and Hartley, SL and , },
title = {Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12582},
pmid = {38623384},
issn = {2352-8729},
abstract = {INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials.

METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years).

RESULTS: In general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory.

DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest.

HIGHLIGHTS: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.},
}

@article {pmid38623383,
year = {2024},
author = {Sukreet, S and Rafii, MS and Rissman, RA},
title = {From understanding to action: Exploring molecular connections of Down syndrome to Alzheimer's disease for targeted therapeutic approach.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12580},
pmid = {38623383},
issn = {2352-8729},
abstract = {Down syndrome (DS) is caused by a third copy of chromosome 21. Alzheimer's disease (AD) is a neurodegenerative condition characterized by the deposition of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain. Both disorders have elevated Aβ, tau, dysregulated immune response, and inflammation. In people with DS, Hsa21 genes like APP and DYRK1A are overexpressed, causing an accumulation of amyloid and neurofibrillary tangles, and potentially contributing to an increased risk of AD. As a result, people with DS are a key demographic for research into AD therapeutics and prevention. The molecular links between DS and AD shed insights into the underlying causes of both diseases and highlight potential therapeutic targets. Also, using biomarkers for early diagnosis and treatment monitoring is an active area of research, and genetic screening for high-risk individuals may enable earlier intervention. Finally, the fundamental mechanistic parallels between DS and AD emphasize the necessity for continued research into effective treatments and prevention measures for DS patients at risk for AD. Genetic screening with customized therapy approaches may help the DS population in current clinical studies and future biomarkers.},
}

@article {pmid38623278,
year = {2024},
author = {Inci, OK and Basırlı, H and Can, M and Yanbul, S and Seyrantepe, V},
title = {Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.},
journal = {Journal of lipids},
volume = {2024},
number = {},
pages = {4530255},
pmid = {38623278},
issn = {2090-3030},
abstract = {Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.},
}

@article {pmid38623052,
year = {2024},
author = {Guzmán-Ocampo, DC and Aguayo-Ortiz, R and Dominguez, L},
title = {Understanding the Modulatory Role of E2012 on the γ-Secretase-Substrate Interaction.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.3c01993},
pmid = {38623052},
issn = {1549-960X},
abstract = {Allosteric modulation plays a critical role in enzyme functionality and requires a deep understanding of the interactions between the active and allosteric sites. γ-Secretase (GS) is a key therapeutic target in the treatment of Alzheimer's disease (AD), through its role in the synthesis of amyloid β peptides that accumulate in AD patients. This study explores the structure and dynamic effects of GS modulation by E2012 binding, employing well-tempered metadynamics and conventional molecular dynamics simulations across three binding scenarios: (1) GS enzyme with and without L458 inhibitor, (2) the GS-substrate complex together with the modulator E2012 in two different binding modes, and (3) E2012 interacting with a C99 substrate fragment. Our findings reveal that the presence of L458 induces conformational changes that contribute to stabilization of the GS enzyme dynamics, previously reported as a key factor that allowed the resolution of the cryo-EM structure and the enhanced binding of E2012. Furthermore, we identified the most favorable binding site for E2012 within the GS-substrate complex, uncovering significant modulatory effects and a complex network of interactions that influence the position of the substrate for catalysis. In addition, we explore a potential substrate-modulator binding before the formation of the enzyme-substrate complex. The insights gained from our study emphasize the importance of these interactions in the development of potential therapeutic interventions that target the functionality of the GS enzyme in AD.},
}

@article {pmid38621897,
year = {2024},
author = {Wang, CH and Wei, XT and Zhao, YQ and Wang, DH and Xue, JJ and Song, ZQ and Tang, F and Liu, RX and Wang, CA},
title = {[Role of NLRP3 inflammasome in prevention and treatment of cognitive impairment-related diseases and traditional Chinese medicine intervention: a review].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {49},
number = {4},
pages = {902-911},
doi = {10.19540/j.cnki.cjcmm.20230913.403},
pmid = {38621897},
issn = {1001-5302},
mesh = {Humans ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Medicine, Chinese Traditional ; Quality of Life ; *Alzheimer Disease/drug therapy/prevention & control ; *Cognitive Dysfunction/drug therapy/prevention & control ; },
abstract = {Alzheimer's disease(AD), vascular dementia(VD), and traumatic brain injury(TBI) are more common cognitive impairment diseases characterized by high disability and mortality rates, imposing a heavy burden on individuals and their families. Although AD, VD, and TBI have different specific mechanisms, their pathogenesis is closely related to the nucleotide-binding oligome-rization domain-like receptor protein 3(NLRP3). The NLRP3 inflammasome is involved in neuroinflammatory responses, mediating microglial polarization, regulating the reduction of amyloid β-protein(Aβ) deposition, neurofibrillary tangles(NFTs) formation, autophagy regulation, and maintaining brain homeostasis, and synaptic stability, thereby contributing to the development of AD, VD, and TBI. Previous studies have shown that traditional Chinese medicine(TCM) can alleviate neuroinflammation, promote microglial polarization towards the M2 phenotype, reduce Aβ deposition and NFTs formation, regulate autophagy, and maintain brain homeostasis by intervening in NLRP3 inflammasome, hence exerting a role in preventing and treating cognitive impairment-related diseases, reducing psychological and economic pressure on patients, and improving their quality of life. Therefore, this article elucidated the role of NLRP3 inflammasome in AD, VS, and TBI, and provided a detailed summary of the latest research results on TCM intervention in NLRP3 inflammasome for the prevention and treatment of these diseases, aiming to inherit the essence of TCM and provide references and foundations for clinical prevention and treatment of cognitive impairment-related diseases with TCM. Meanwhile, this also offers insights and directions for further research in TCM for the prevention and treatment of cognitive impairment-related diseases.},
}

Humans
Inflammasomes/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
Amyloid beta-Peptides/metabolism
Medicine, Chinese Traditional
Quality of Life
*Alzheimer Disease/drug therapy/prevention & control
*Cognitive Dysfunction/drug therapy/prevention & control

@article {pmid38621736,
year = {2024},
author = {Cheng, L and Zhu, C and Zhou, B and Zhang, J and Wang, C and Song, R and Tao, L},
title = {Visual analysis on the study status and trends of acupuncture and moxibustion for Alzheimer's disease.},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {44},
number = {4},
pages = {469-478},
doi = {10.13703/j.0255-2930.20230721-k0003},
pmid = {38621736},
issn = {0255-2930},
mesh = {Animals ; Mice ; *Moxibustion ; *Alzheimer Disease/therapy ; *Acupuncture Therapy ; *Electroacupuncture ; Acupuncture Points ; },
abstract = {The research history, hot spots and frontier trends of acupuncture and moxibustion for Alzheimer's disease (AD) were explored using knowledge graph technology. The articles on acupuncture and moxibustion for AD were searched from 6 databases, i.e. CNKI, VIP, Wanfang, SinoMed, Pubmed and Web of Science, from January 1st, 1993 to January 1st, 2023. Using CiteSpace6.2.R2 Advance and VOSviewer V1.6.19 softwares, the knowledge map was graphed and the visual analysis was performed. A total of 1 228 Chinese and 309 English articles were included. The high-frequency keywords were generally divided into the keywords of clinical diseases (AD, dementia), those of therapeutic methods (electroacupuncture, acupuncture-moxibustion and acupuncture) and those of mechanism study (β-amyloid, mice). Thirteen keyword clusters were formed among the articles of Chinese version, e.g. acupuncture-moxibustion, dementia, acupuncture and electroacupuncture; and 8 clusters were obtained among English articles, e.g. electroacupuncture, drug therapy and hippocampus. The high-frequency keywords of acupoints included Baihui (GV 20), Dazhui (GV 14), Yintang (GV 24[+]), Zusanli (ST 36), Fenglong (ST 40), etc. Six clusters of "acupuncture techniques → acupoints" were obtained for the treatment of AD with acupuncture and moxibustion. The therapeutic methods and modes of AD with acupuncture and moxibustion are constantly progressed, the development of clinical research tends to the evaluation of novel therapeutic mode and clinical effect, and the mechanism of acupuncture and moxibustion for the effect on AD are more deeply explored. Among the various therapeutic methods, acupuncture-moxibustion, acupuncture and electroacupuncture have been early predominant; while, many novel methods are gradually displayed later, such as music electroacupuncture and hydro-acupuncture. In recent 30 years, among Chinese and English articles for the studies of AD treated with acupuncture and moxibustion, the theme of them focuses on the two aspects, the observation of clinical effect and the mechanism research. It is found that the clinical therapeutic methods have been gradually improved and the mechanism exploration been deepened.},
}

Animals
Mice
*Moxibustion
*Alzheimer Disease/therapy
*Acupuncture Therapy
*Electroacupuncture
Acupuncture Points

@article {pmid38619479,
year = {2024},
author = {Pang, S and Chen, N and Li, Z and Luo, ZH and Dong, W and Gao, S and Liu, N and Pan, S and Zhang, LF and Chen, J and Yang, YJ},
title = {Discovery of palmatine derivatives as potent neuroprotective agents.},
journal = {Journal of Asian natural products research},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/10286020.2024.2341927},
pmid = {38619479},
issn = {1477-2213},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by the presence of neurodegenerative lesions and cognitive impairment. In this study, a series of novel palmatine derivatives were designed and synthesized through the introduction of a heteroatom using carbodiimide-mediated condensation. The synthesized compounds were then screened for toxicity and potency, leading to the identification of compound 2q, which exhibited low toxicity and high potency. Our findings demonstrated that compound 2q displayed significant neuroprotective activity in vitro, emerging as a promising candidate for Alzheimer's disease treatment.},
}

@article {pmid38617987,
year = {2024},
author = {Liu, ZL and Hua, FF and Qu, L and Yan, N and Zhang, HF},
title = {Evaluating serum CXCL12, sCD22, Lp-PLA2 levels and ratios as biomarkers for diagnosis of Alzheimer's disease.},
journal = {World journal of psychiatry},
volume = {14},
number = {3},
pages = {380-387},
pmid = {38617987},
issn = {2220-3206},
abstract = {BACKGROUND: Grasping the underlying mechanisms of Alzheimer's disease (AD) is still a work in progress, and existing diagnostic techniques encounter various obstacles. Therefore, the discovery of dependable biomarkers is essential for early detection, tracking the disease's advancement, and steering treatment strategies.

AIM: To explore the diagnostic potential of serum CXCL12, sCD22, Lp-PLA2, and their ratios in AD, aiming to enhance early detection and inform targeted treatment strategies.

METHODS: The study was conducted in Dongying people's Hospital from January 2021 to December 2022. Participants included 60 AD patients (AD group) and 60 healthy people (control group). Using a prospective case-control design, the levels of CXCL12, sCD22 and Lp-PLA2 and their ratios were detected by enzyme-linked immunosorbent assay kit in the diagnosis of AD. The differences between the two groups were analyzed by statistical methods, and the corresponding ratio was constructed to improve the specificity and sensitivity of diagnosis.

RESULTS: Serum CXCL12 levels were higher in the AD group (47.2 ± 8.5 ng/mL) than the control group (32.8 ± 5.7 ng/mL, P < 0.001), while sCD22 levels were lower (14.3 ± 2.1 ng/mL vs 18.9 ± 3.4 ng/mL, P < 0.01). Lp-PLA2 levels were also higher in the AD group (112.5 ± 20.6 ng/mL vs 89.7 ± 15.2 ng/mL, P < 0.05). Significant differences were noted in CXCL12/sCD22 (3.3 vs 1.7, P < 0.001) and Lp-PLA2/sCD22 ratios (8.0 vs 5.2, P < 0.05) between the groups. Receiver operating characteristic analysis confirmed high sensitivity and specificity of these markers and their ratios in distinguishing AD, with area under the curves ranging from 0.568 to 0.787.

CONCLUSION: Serum CXCL12 and Lp-PLA2 levels were significantly increased, while sCD22 were significantly decreased, as well as increases in the ratios of CXCL12/sCD22 and Lp-PLA2/sCD22, are closely related to the onset of AD. These biomarkers and their ratios can be used as potential diagnostic indicators for AD, providing an important clinical reference for early intervention and treatment.},
}

@article {pmid38617712,
year = {2024},
author = {Nawar, NF and Beltagy, DM and Mohamed, TM and Tousson, E and El-Keey, MM},
title = {Ameliorative anti-coagulant, anti-oxidative and anti-ferroptotic activities of nanocurcumin and donepezil on coagulation, oxidation and ferroptosis in Alzheimer's disease.},
journal = {Toxicology research},
volume = {13},
number = {2},
pages = {tfae054},
pmid = {38617712},
issn = {2045-452X},
abstract = {Alzheimer's disease (ad) is a neurological condition that worsens over time and is characterized by the buildup of amyloid (Aβ) plaques in the brain parenchyma. Neuroprotection and cholinesterase inhibition have been the two primary techniques used in the creation of medications to date. In ad, a novel sort of programmed cell death known as ferroptosis takes place along with iron buildup, lipid peroxidation, and glutathione deficiency. The objective of the current investigation was to examine the neuroprotective and anti-ferroptotic role of nanocurcumin and Donepezil against model of aluminum chloride AlCl3 and D-galactose induced ad. The experiment was performed on 70 rats divided into (G1: control, G2: NCMN, G3: Donepezil, G4: ad-model, G5: Donepezil co-treatment, G6: NCMN co-treatment and G7: NCMN+Donepezil co-treatment). Hematological parameters and biochemical investigations as oxidative stress, liver function, kidney function, iron profile and plasma fibrinogen were evaluated. Treatment with Nanocurcumin alone or in combination with Donepezil improved oxidative stress, liver functions, and kidney functions, improve iron profile and decreased plasma fibrinogen.},
}

@article {pmid38617639,
year = {2024},
author = {Sutthibutpong, T and Posansee, K and Liangruksa, M and Termsaithong, T and Piyayotai, S and Phitsuwan, P and Saparpakorn, P and Hannongbua, S and Laomettachit, T},
title = {Combining Deep Learning and Structural Modeling to Identify Potential Acetylcholinesterase Inhibitors from Hericium erinaceus.},
journal = {ACS omega},
volume = {9},
number = {14},
pages = {16311-16321},
pmid = {38617639},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is the most common type of dementia, affecting over 50 million people worldwide. Currently, most approved medications for AD inhibit the activity of acetylcholinesterase (AChE), but these treatments often come with harmful side effects. There is growing interest in the use of natural compounds for disease prevention, alleviation, and treatment. This trend is driven by the anticipation that these substances may incur fewer side effects than existing medications. This research presents a computational approach combining machine learning with structural modeling to discover compounds from medicinal mushrooms with a high potential to inhibit the activity of AChE. First, we developed a deep neural network capable of rapidly screening a vast number of compounds to indicate their potential to inhibit AChE activity. Subsequently, we applied deep learning models to screen the compounds in the BACMUSHBASE database, which catalogs the bioactive compounds from cultivated and wild mushroom varieties local to Thailand, resulting in the identification of five promising compounds. Next, the five identified compounds underwent molecular docking techniques to calculate the binding energy between the compounds and AChE. This allowed us to refine the selection to two compounds, erinacerin A and hericenone B. Further analysis of the binding energy patterns between these compounds and the target protein revealed that both compounds displayed binding energy profiles similar to the combined characteristics of donepezil and galanthamine, the prescription drugs for AD. We propose that these two compounds, derived from Hericium erinaceus (also known as lion's mane mushroom), are suitable candidates for further research and development into symptom-alleviating AD medications.},
}

@article {pmid38617279,
year = {2024},
author = {Li, X and Chen, J and Yang, Y and Cai, H and Ao, Z and Xing, Y and Li, K and Yang, K and Wallace, A and Friend, J and Lee, LP and Wang, N and Guo, F},
title = {Extracellular vesicles-based point-of-care testing for the diagnosis and monitoring of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.03.31.587511},
pmid = {38617279},
abstract = {Alzheimer's disease (AD) is a debilitating condition that affects millions of people worldwide. One promising strategy for detecting and monitoring AD early on is using extracellular vesicles (EVs)-based point-of-care testing; however, diagnosing AD using EVs poses a challenge due to the low abundance of EV-biomarkers. Here, we present a fully integrated organic electrochemical transistor (OECT) that enables high accuracy, speed, and convenience in the detection of EVs from AD patients. We incorporated self-aligned acoustoelectric enhancement of EVs on a chip that rapidly propels, enriches, and specifically binds EVs to the OECT detection area. With our enhancement of pre-concentration, we increased the sensitivity to a limit of detection of 500 EV particles/μL and reduced the required detection time to just two minutes. We also tested the sensor on an AD mouse model to monitor AD progression, examined mouse Aβ EVs at different time courses, and compared them with intraneuronal Aβ cumulation using MRI. This innovative technology has the potential to diagnose Alzheimer's and other neurodegenerative diseases accurately and quickly, enabling monitoring of disease progression and treatment response.},
}

@article {pmid38617189,
year = {2024},
author = {Strohl, WR},
title = {Structure and function of therapeutic antibodies approved by the US FDA in 2023.},
journal = {Antibody therapeutics},
volume = {7},
number = {2},
pages = {132-156},
pmid = {38617189},
issn = {2516-4236},
abstract = {In calendar year 2023, the United States Food and Drug Administration (US FDA) approved a total of 55 new molecular entities, of which 12 were in the class of therapeutic antibodies. Besides antibody protein drugs, the US FDA also approved another five non-antibody protein drugs, making the broader class of protein drugs about 31% of the total approved drugs. Among the 12 therapeutic antibodies approved by the US FDA, 8 were relatively standard IgG formats, 3 were bivalent, bispecific antibodies and 1 was a trivalent, bispecific antibody. In 2023, no new antibody-drug conjugates, immunocytokines or chimeric antigen receptor-T cells were approved. Of the approved antibodies, two targeted programmed cell death receptor-1 (PD-1) for orphan indications, two targeted CD20 for diffuse large B cell lymphoma, two targeted different receptors (B-cell maturation antigen [BCMA] and G-coupled protein receptor class C, group 5, member D [GPRC5D]) for treatment of multiple myeloma, and one each that targeted amyloid-β protofibrils for Alzheimer's disease, neonatal Fc receptor alpha-chain for myasthenia gravis, complement factor C5 for CD55 deficiency with hyper-activation of complement, angiopathic thrombosis and severe protein-losing enteropathy disease, interleukin (IL)-23p19 for severely active ulcerative colitis, IL-17A-F for plaque psoriasis and respiratory syncytial virus (RSV)-F protein for season-long RSV prophylaxis in infants.},
}

@article {pmid38616958,
year = {2024},
author = {Goal, A and Raj, K and Singh, S and Arora, R},
title = {Protective effects of Embelin in Benzo[α]pyrene induced cognitive and memory impairment in experimental model of mice.},
journal = {Current research in neurobiology},
volume = {6},
number = {},
pages = {100122},
pmid = {38616958},
issn = {2665-945X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that affects the neurons in the hippocampus, resulting in cognitive and memory impairment. The most prominent clinical characteristics of AD are the production of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation in neurons. It has been proven that embelin (Emb) possesses antioxidant, anti-inflammatory, and neuroprotective properties. Therefore, we assessed the therapeutic potential of Emb in Benzo [α]pyrene (BaP)-induced cognitive impairment in experimental mice. BaP (5 mg/kg, i. p) was given to mice daily for 28 days, and Emb (2.5, 5, and 10 mg/kg, i. p) was given from 14 to 28 days of a protocol. In addition, locomotor activity was evaluated using open-field and spatial working, and non-spatial memory was evaluated using novel object recognition tasks (NORT), Morris water maze (MWM), and Y- maze. At the end of the study, the animal tissue homogenate was used to check biochemicals, neuroinflammation, and neurotransmitter changes. BaP-treated mice showed a significant decline in locomotor activity, learning and memory deficits and augmented oxidative stress (lipid peroxidation, nitrite, and GSH). Further, BaP promoted the release of inflammatory tissue markers, decreased acetylcholine, dopamine, GABA, serotonin, and norepinephrine, and increased glutamate concentration. However, treatment with Emb at dose-dependently prevented biochemical changes, improved antioxidant levels, reduced neuroinflammation, restored neurotransmitter concentration, and inhibited the NF-κB pathway. The current study's finding suggested that Emb improved cognitive functions through antioxidant, anti-inflammatory, and neuroprotective mechanisms and inhibition of acetylcholinesterase (AChE) enzyme activities and Aβ-42 accumulation.},
}

@article {pmid38616755,
year = {2024},
author = {Arora, R and Baldi, A},
title = {Revolutionizing Neurological Disorder Treatment: Integrating Innovations in Pharmaceutical Interventions and Advanced Therapeutic Technologies.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128284824240328071911},
pmid = {38616755},
issn = {1873-4286},
abstract = {Neurological disorders impose a significant burden on individuals, leading to disabilities and a reduced quality of life. However, recent years have witnessed remarkable advancements in pharmaceutical interventions aimed at treating these disorders. This review article aims to provide an overview of the latest innovations and breakthroughs in neurological disorder treatment, with a specific focus on key therapeutic areas such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and stroke. This review explores emerging trends in drug development, including the identification of novel therapeutic targets, the development of innovative drug delivery systems, and the application of personalized medicine approaches. Furthermore, it highlights the integration of advanced therapeutic technologies such as gene therapy, optogenetics, and neurostimulation techniques. These technologies hold promise for precise modulation of neural circuits, restoration of neuronal function, and even disease modification. While these advancements offer hopeful prospects for more effective and tailored treatments, challenges such as the need for improved diagnostic tools, identification of new targets for intervention, and optimization of drug delivery methods remain. By addressing these challenges and continuing to invest in research and collaboration, we can revolutionize the treatment of neurological disorders and significantly enhance the lives of those affected by these conditions.},
}

@article {pmid38616356,
year = {2024},
author = {Azzini, E and Peña-Corona, SI and Hernández-Parra, H and Chandran, D and Saleena, LAK and Sawikr, Y and Peluso, I and Dhumal, S and Kumar, M and Leyva-Gómez, G and Martorell, M and Sharifi-Rad, J and Calina, D},
title = {Neuroprotective and anti-inflammatory effects of curcumin in Alzheimer's disease: Targeting neuroinflammation strategies.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.8200},
pmid = {38616356},
issn = {1099-1573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta plaques and neurofibrillary tangles, leading to neuronal loss. Curcumin, a polyphenolic compound derived from Curcuma longa, has shown potential neuroprotective effects due to its anti-inflammatory and antioxidant properties. This review aims to synthesize current preclinical data on the anti-neuroinflammatory mechanisms of curcumin in the context of AD, addressing its pharmacokinetics, bioavailability, and potential as a therapeutic adjunct. An exhaustive literature search was conducted, focusing on recent studies within the last 10 years related to curcumin's impact on neuroinflammation and its neuroprotective role in AD. The review methodology included sourcing articles from specialized databases using specific medical subject headings terms to ensure precision and relevance. Curcumin demonstrates significant neuroprotective properties by modulating neuroinflammatory pathways, scavenging reactive oxygen species, and inhibiting the production of pro-inflammatory cytokines. Despite its potential, challenges remain regarding its limited bioavailability and the scarcity of comprehensive human clinical trials. Curcumin emerges as a promising therapeutic adjunct in AD due to its multimodal neuroprotective benefits. However, further research is required to overcome challenges related to bioavailability and to establish effective dosing regimens in human subjects. Developing novel delivery systems and formulations may enhance curcumin's therapeutic potential in AD treatment.},
}

@article {pmid38616258,
year = {2024},
author = {D'Acunzo, P and Argyrousi, EK and Ungania, JM and Kim, Y and DeRosa, S and Pawlik, M and Goulbourne, CN and Arancio, O and Levy, E},
title = {Mitovesicles secreted into the extracellular space of brains with mitochondrial dysfunction impair synaptic plasticity.},
journal = {Molecular neurodegeneration},
volume = {19},
number = {1},
pages = {34},
pmid = {38616258},
issn = {1750-1326},
support = {AG017617/AG/NIA NIH HHS/United States ; AG056732/AG/NIA NIH HHS/United States ; AG057517/AG/NIA NIH HHS/United States ; DA044489/DA/NIDA NIH HHS/United States ; R01NS110024/NH/NIH HHS/United States ; AARF-22-923826/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Animals ; Mice ; Extracellular Space ; *Down Syndrome ; Neuronal Plasticity ; Brain ; *Alzheimer Disease ; Disease Models, Animal ; Monoamine Oxidase ; *Mitochondrial Diseases ; },
abstract = {BACKGROUND: Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer's disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved.

METHODS: Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices.

RESULTS: Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP.

CONCLUSIONS: Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.},
}

Humans
Animals
Mice
Extracellular Space
*Down Syndrome
Neuronal Plasticity
Brain
*Alzheimer Disease
Disease Models, Animal
Monoamine Oxidase
*Mitochondrial Diseases

@article {pmid38616003,
year = {2024},
author = {Xiang, X and Xia, S and Li, S and Zeng, Y and Wang, L and Zhou, Y},
title = {Study on the role and mechanism of Tan IIA in Alzheimer's disease based on CREB-BDNF-TrkB pathway.},
journal = {Neuroscience letters},
volume = {830},
number = {},
pages = {137769},
doi = {10.1016/j.neulet.2024.137769},
pmid = {38616003},
issn = {1872-7972},
abstract = {The occurrence and development of Alzheimer's disease (AD) is closely related to neuronal loss, inflammatory response, cholinergic imbalance, and Tau protein hyperphosphorylation. Previous studies have confirmed that Streptozotocin (STZ) can be used to establish a rat model of AD by injecting it into the rat brain via the lateral ventricle. Our previous research showed that Danshentone IIA (Tan IIA) can improve cognitive dysfunction in rats caused by CC chemokine ligand 2, and network pharmacology results show that Tan IIA is very likely to improve AD symptoms through the cyclic adenosine monophosphate response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor protein (TrkB) pathway. The results of the water maze experiment showed that after Tan IIA treatment, the escape latency of AD rats was shortened and the number of platform crossings increased; in the new object recognition experiment, the discrimination index of AD rats significantly increased after treatment; Nissl staining and Tunel staining results showed that Tan IIA increased the number of surviving neurons in the hippocampus of cognitively impaired rats and reduced neuronal apoptosis; Bielschowsky silver staining results showed that Tan IIA reduced neurofibrillary tangles (NFTs) in the AD rats; Tan IIA can reduce the inflammatory response and oxidative stress reaction in the hippocampus of AD rats, and at the same time reduce the activity of acetylcholinesterase. Tan IIA can significantly increase the expression of CREB, BDNF, TrkB in the hippocampal tissue of STZ-injured rats (P < 0.05). These data suggest that Tan IIA may upregulate the expression of the CREB-BDNF-TrkB signaling pathway in the hippocampus of brain tissue, produce anti-neuroinflammatory, antioxidant stress, inhibit neuronal apoptosis effects, and improve cholinergic neurotransmitter disorder induced by STZ, reduce the neuronal damage and learning and memory impairment caused by STZ in rats, and improve the cognitive function of rats.},
}

@article {pmid38615895,
year = {2024},
author = {Rajendran, K and Krishnan, UM},
title = {Mechanistic insights and emerging therapeutic stratagems for Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102309},
doi = {10.1016/j.arr.2024.102309},
pmid = {38615895},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), a multi-factorial neurodegenerative disorder has affected over 30 million individuals globally and these numbers are expected to increase in the coming decades. Current therapeutic interventions are largely ineffective as they focus on a single target. Development of an effective drug therapy requires a deep understanding of the various factors influencing the onset and progression of the disease. Aging and genetic factors exert a major influence on the development of AD. Other factors like post-viral infections, iron overload, gut dysbiosis, and vascular dysfunction also exacerbate the onset and progression of AD. Further, post-translational modifications in tau, DRP1, CREB, and p65 proteins increase the disease severity through triggering mitochondrial dysfunction, synaptic loss, and differential interaction of amyloid beta with different receptors leading to impaired intracellular signalling. With advancements in neuroscience tools, new inter-relations that aggravate AD are being discovered including pre-existing diseases and exposure to other pathogens. Simultaneously, new therapeutic strategies involving modulation of gene expression through targeted delivery or modulation with light, harnessing the immune response to promote clearance of amyloid deposits, introduction of stem cells and extracellular vesicles to replace the destroyed neurons, exploring new therapeutic molecules from plant, marine and biological sources delivered in the free state or through nanoparticles and use of non-pharmacological interventions like music, transcranial stimulation and yoga. Polypharmacology approaches involving combination of therapeutic agents are also under active investigation for superior therapeutic outcomes. This review elaborates on various disease-causing factors, their underlying mechanisms, the inter-play between different disease-causing players, and emerging therapeutic options including those under clinical trials, for treatment of AD. The challenges involved in AD therapy and the way forward have also been discussed.},
}

@article {pmid38614372,
year = {2024},
author = {Hari, I and Adeyemi, OF and Gowland, P and Bowtell, R and Mougin, O and Vesey, P and Shah, J and Mukaetova-Ladinska, EB and Hosseini, AA},
title = {Memory Impairment in Amyloidβ-status Alzheimer's disease is associated with a reduction in CA1 and dentate gyrus volume: in vivo MRI at 7T.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {120607},
doi = {10.1016/j.neuroimage.2024.120607},
pmid = {38614372},
issn = {1095-9572},
abstract = {INTRODUCTION: In Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The neuropsychological battery of the Uniform Data Set (UDSNB3.0) assesses cognition in ageing and dementia, by measuring scores across different cognitive domains such as attention, memory, processing speed, executive function and language. However, its neuroanatomical correlates have not been investigated using 7 Tesla MRI (7T MRI).

METHODS: We used 7T MRI to investigate the correlations between hippocampal subfield volumes and the UDSNB3.0 in 24 individuals with Amyloidβ-status AD and 18 age-matched controls, with respective age ranges of 60 (42-76) and 62 (52-79) years. AD participants with a Medial Temporal Atrophy scale of higher than 2 on 3T MRI were excluded from the study.

RESULTS: A significant difference in the entire hippocampal volume was observed in the AD group compared to healthy controls (HC), primarily influenced by CA1, the largest hippocampal subfield. Notably, no significant difference in whole brain volume between the groups implies that hippocampal volume loss is not merely reflective of overall brain atrophy. UDSNB3.0 cognitive scores showed significant differences between AD and HC, particularly in Memory, Language, and Visuospatial domains. DG volume was sigificantly associated with UDSNB3.0 Memory and Executive domain scores for AD patients. The data also suggested a non significant trend for CA1 volume associated with UDSNB3.0 Memory, Executive, and Language domain scores in AD. A reassessment focused on hippocampal subfields and MoCA memory subdomains in AD, demonstrated associations with DG showing with Cued, Uncued, and Recognition Memory subscores, while CA1 and Tail displayed associations solely with Cued memory.

DISCUSSION: This study reveals differences in the hippocampal volumes measured using 7T MRI, between individuals with early symptomatic AD compared with healthy controls. This highlights the potential of 7T MRI as a valuable tool for early AD diagnosis and the real-time monitoring of AD progression and treatment efficacy.

CLINICALTRIALS: GOV: ID NCT04992975 (Clinicaltrial.gov 2023).},
}

@article {pmid38614367,
year = {2024},
author = {Roghani, AK and Garcia, RI and Roghani, A and Reddy, A and Khemka, S and Reddy, RP and Pattoor, V and Jacob, M and Reddy, PH and Sehar, U},
title = {Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.},
journal = {Ageing research reviews},
volume = {97},
number = {},
pages = {102291},
doi = {10.1016/j.arr.2024.102291},
pmid = {38614367},
issn = {1872-9649},
abstract = {The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.},
}

@article {pmid38612872,
year = {2024},
author = {Bai, X and Zhao, X and Liu, K and Yang, X and He, Q and Gao, Y and Li, W and Han, W},
title = {Mulberry Leaf Compounds and Gut Microbiota in Alzheimer's Disease and Diabetes: A Study Using Network Pharmacology, Molecular Dynamics Simulation, and Cellular Assays.},
journal = {International journal of molecular sciences},
volume = {25},
number = {7},
pages = {},
pmid = {38612872},
issn = {1422-0067},
support = {20230508072RC//Jilin Province Science and Technology Department/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy ; Kaempferols ; *Morus ; *Gastrointestinal Microbiome ; Molecular Dynamics Simulation ; Network Pharmacology ; *Alzheimer Disease/drug therapy ; Molecular Docking Simulation ; Fruit ; Flavonoids ; },
abstract = {Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer's disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry leaf offer therapeutic effects for relieving diabetic symptoms and providing neuroprotection. However, the mechanisms of this effect have not been fully elucidated. This investigation aimed to investigate the combined effects of specific mulberry leaf flavonoids (kaempferol, quercetin, rhamnocitrin, tetramethoxyluteolin, and norartocarpetin) on both type 2 diabetes mellitus (T2DM) and AD. Additionally, the role of the gut microbiota in these two diseases' treatment was studied. Using network pharmacology, we investigated the potential mechanisms of flavonoids in mulberry leaves, combined with gut microbiota, in combating AD and T2DM. In addition, we identified protein tyrosine phosphatase 1B (PTP1B) as a key target for kaempferol in these two diseases. Molecular docking and molecular dynamics simulations showed that kaempferol has the potential to inhibit PTP1B for indirect treatment of AD, which was proven by measuring the IC50 of kaempferol (279.23 μM). The cell experiment also confirmed the dose-dependent effect of kaempferol on the phosphorylation of total cellular protein in HepG2 cells. This research supports the concept of food-medicine homology and broadens the range of medical treatments for diabetes and AD, highlighting the prospect of integrating traditional herbal remedies with modern medical research.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy
Kaempferols
*Morus
*Gastrointestinal Microbiome
Molecular Dynamics Simulation
Network Pharmacology
*Alzheimer Disease/drug therapy
Molecular Docking Simulation
Fruit
Flavonoids

@article {pmid38612861,
year = {2024},
author = {Kanwal, H and Sangineto, M and Ciarnelli, M and Castaldo, P and Villani, R and Romano, AD and Serviddio, G and Cassano, T},
title = {Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {25},
number = {7},
pages = {},
pmid = {38612861},
issn = {1422-0067},
mesh = {United States ; Animals ; Mice ; *Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; *Neurodegenerative Diseases ; Endocannabinoids ; Neuroinflammatory Diseases ; },
abstract = {Alzheimer's disease (AD), the most common neurodegenerative disease (NDD), is characterized by chronic neuronal cell death through progressive loss of cognitive function. Amyloid beta (Aβ) deposition, neuroinflammation, oxidative stress, and hyperphosphorylated tau proteins are considered the hallmarks of AD pathology. Different therapeutic approaches approved by the Food and Drug Administration can only target a single altered pathway instead of various mechanisms that are involved in AD pathology, resulting in limited symptomatic relief and almost no effect in slowing down the disease progression. Growing evidence on modulating the components of the endocannabinoid system (ECS) proclaimed their neuroprotective effects by reducing neurochemical alterations and preventing cellular dysfunction. Recent studies on AD mouse models have reported that the inhibitors of the fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAGL), hydrolytic enzymes for N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, might be promising candidates as therapeutical intervention. The FAAH and MAGL inhibitors alone or in combination seem to produce neuroprotection by reversing cognitive deficits along with Aβ-induced neuroinflammation, oxidative responses, and neuronal death, delaying AD progression. Their exact signaling mechanisms need to be elucidated for understanding the brain intrinsic repair mechanism. The aim of this review was to shed light on physiology and pathophysiology of AD and to summarize the experimental data on neuroprotective roles of FAAH and MAGL inhibitors. In this review, we have also included CB1R and CB2R modulators with their diverse roles to modulate ECS mediated responses such as anti-nociceptive, anxiolytic, and anti-inflammatory actions in AD. Future research would provide the directions in understanding the molecular mechanisms and development of new therapeutic interventions for the treatment of AD.},
}

United States
Animals
Mice
*Alzheimer Disease/drug therapy
Amyloid beta-Peptides
*Neurodegenerative Diseases
Endocannabinoids
Neuroinflammatory Diseases

@article {pmid38612804,
year = {2024},
author = {Giri, PM and Banerjee, A and Ghosal, A and Layek, B},
title = {Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications.},
journal = {International journal of molecular sciences},
volume = {25},
number = {7},
pages = {},
pmid = {38612804},
issn = {1422-0067},
support = {2P20M109024/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Neuroinflammatory Diseases ; Inflammation/therapy ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; },
abstract = {Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.},
}

Humans
Neuroinflammatory Diseases
Inflammation/therapy
*Alzheimer Disease
*Amyotrophic Lateral Sclerosis
Central Nervous System

@article {pmid38612775,
year = {2024},
author = {McMillan, IO and Gearing, M and Wang, L},
title = {Vascular Heparan Sulfate and Amyloid-β in Alzheimer's Disease Patients.},
journal = {International journal of molecular sciences},
volume = {25},
number = {7},
pages = {},
pmid = {38612775},
issn = {1422-0067},
support = {1RF1AG074289-01, 1RF1AG069039-01, and P30AG066511//National Institute of Health/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/genetics ; *Neurodegenerative Diseases ; Apolipoprotein E4/genetics ; Amyloid beta-Peptides ; *Cerebral Amyloid Angiopathy ; Heparitin Sulfate ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of extracellular amyloid-β peptides (Aβ) within the cerebral parenchyma and vasculature, which is known as cerebral amyloid angiopathy (CAA). This study utilized confocal imaging to investigate heparan sulfate (HS) expression within the cerebrovasculature and its associations with Aβ, gender, and ApoE4 genotype in AD. Our investigation revealed elevated levels of HS in the cerebrovasculature of AD patients with severe CAA. Additionally, these patients exhibited higher HS colocalization with Aβ in the cerebrovasculature, including both endothelial and vascular smooth muscle cell compartments. Intriguingly, a reversal in the polarized expression of HS within the cerebrovasculature was detected in AD patients with severe CAA. Furthermore, male patients exhibited lower levels of both parenchymal and cerebrovascular HS. Additionally, ApoE4 carriers displayed heightened cerebrovascular Aβ expression and a tendency of elevated cerebrovascular HS levels in AD patients with severe CAA. Overall, these findings reveal potential intricate interplay between HS, Aβ, ApoE, and vascular pathology in AD, thereby underscoring the potential roles of cerebrovascular HS in CAA development and AD pathology. Further study of the underlying mechanisms may present novel therapeutic avenues for AD treatment.},
}

Humans
Male
*Alzheimer Disease/genetics
*Neurodegenerative Diseases
Apolipoprotein E4/genetics
Amyloid beta-Peptides
*Cerebral Amyloid Angiopathy
Heparitin Sulfate

@article {pmid38612729,
year = {2024},
author = {Hsu, CC and Wang, SI and Lin, HC and Lin, ES and Yang, FP and Chang, CM and Wei, JC},
title = {Difference of Cerebrospinal Fluid Biomarkers and Neuropsychiatric Symptoms Profiles among Normal Cognition, Mild Cognitive Impairment, and Dementia Patient.},
journal = {International journal of molecular sciences},
volume = {25},
number = {7},
pages = {},
pmid = {38612729},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Affect ; Amyloidogenic Proteins ; Biomarkers ; Cognition ; },
abstract = {The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-β42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer's Coordinating Center's Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-β42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer's disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-β at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aβ-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aβ-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer's patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies.},
}

Humans
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Affect
Amyloidogenic Proteins
Biomarkers
Cognition

@article {pmid38612719,
year = {2024},
author = {Fessel, J},
title = {Personalized, Precision Medicine to Cure Alzheimer's Dementia: Approach #1.},
journal = {International journal of molecular sciences},
volume = {25},
number = {7},
pages = {},
pmid = {38612719},
issn = {1422-0067},
mesh = {Humans ; Animals ; Female ; Male ; *Precision Medicine ; *Alzheimer Disease/drug therapy ; Brain ; Risk Factors ; Uncertainty ; Randomized Controlled Trials as Topic ; },
abstract = {The goal of the treatment for Alzheimer's dementia (AD) is the cure of dementia. A literature review revealed 18 major elements causing AD and 29 separate medications that address them. For any individual with AD, one is unlikely to discern which major causal elements produced dementia. Thus, for personalized, precision medicine, all causal elements must be treated so that each individual patient will have her or his causal elements addressed. Twenty-nine drugs cannot concomitantly be administered, so triple combinations of drugs taken from that list are suggested, and each triple combination can be administered sequentially, in any order. Ten combinations given over 13 weeks require 2.5 years, or if given over 26 weeks, they require 5.0 years. Such sequential treatment addresses all 18 elements and should cure dementia. In addition, any comorbid risk factors for AD whose first presence or worsening was within ±1 year of when AD first appeared should receive appropriate, standard treatment together with the sequential combinations. The article outlines a randomized clinical trial that is necessary to assess the safety and efficacy of the proposed treatments; it includes a triple-drug Rx for equipoise. Clinical trials should have durations of both 2.5 and 5.0 years unless the data safety monitoring board (DSMB) determines earlier success or futility since it is uncertain whether three or six months of treatment will be curative in humans, although studies in animals suggest that the briefer duration of treatment might be effective and restore defective neural tracts.},
}

Humans
Animals
Female
Male
*Precision Medicine
*Alzheimer Disease/drug therapy
Brain
Risk Factors
Uncertainty
Randomized Controlled Trials as Topic

@article {pmid38612701,
year = {2024},
author = {Høilund-Carlsen, PF and Alavi, A and Castellani, RJ and Neve, RL and Perry, G and Revheim, ME and Barrio, JR},
title = {Alzheimer's Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?.},
journal = {International journal of molecular sciences},
volume = {25},
number = {7},
pages = {},
pmid = {38612701},
issn = {1422-0067},
mesh = {United States ; Humans ; *Alzheimer Disease/therapy ; Ice Cover ; Amyloidogenic Proteins ; Radioimmunotherapy ; *Antibodies, Monoclonal, Humanized ; },
abstract = {The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.},
}

United States
Humans
*Alzheimer Disease/therapy
Ice Cover
Amyloidogenic Proteins
Radioimmunotherapy
*Antibodies, Monoclonal, Humanized

@article {pmid38611758,
year = {2024},
author = {Chen, H and Zeng, Y and Wang, D and Li, Y and Xing, J and Zeng, Y and Liu, Z and Zhou, X and Fan, H},
title = {Neuroinflammation of Microglial Regulation in Alzheimer's Disease: Therapeutic Approaches.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {7},
pages = {},
pmid = {38611758},
issn = {1420-3049},
support = {2022A1515010974//Natural Science Foundation of Guangdong Province/ ; 202201010387//Science and Technology Program of Guangzhou/ ; 2022KTSCX059//the Scientific Research and Cultivation Foundation for young teachers of pharmacy of Guangdong Pharmaceutical University, the Scientific Research Projects (Characteristic Innovation) of General Universities in Guangdong Province/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Microglia ; Neuroinflammatory Diseases ; Central Nervous System ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system that is clinically characterized by a progressive decline in memory and cognitive function. The pathogenesis of AD is intricate and not yet fully understood. Neuroinflammation, particularly microglial activation-mediated neuroinflammation, is believed to play a crucial role in increasing the risk, triggering the onset, and hastening the progression of AD. Modulating microglial activation and regulating microglial energy metabolic disorder are seen as promising strategies to intervene in AD. The application of anti-inflammatory drugs and the targeting of microglia for the prevention and treatment of AD has emerged as a new area of research interest. This article provides a comprehensive review of the role of neuroinflammation of microglial regulation in the development of AD, exploring the connection between microglial energy metabolic disorder, neuroinflammation, and AD development. Additionally, the advancements in anti-inflammatory and microglia-regulating therapies for AD are discussed.},
}

Humans
*Alzheimer Disease/drug therapy
Microglia
Neuroinflammatory Diseases
Central Nervous System
Anti-Inflammatory Agents/pharmacology/therapeutic use

@article {pmid38611617,
year = {2024},
author = {Colvee-Martin, H and Parra, JR and Gonzalez, GA and Barker, W and Duara, R},
title = {Neuropathology, Neuroimaging, and Fluid Biomarkers in Alzheimer's Disease.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {14},
number = {7},
pages = {},
pmid = {38611617},
issn = {2075-4418},
support = {P30AG066506-01/NH/NIH HHS/United States ; },
abstract = {An improved understanding of the pathobiology of Alzheimer's disease (AD) should lead ultimately to an earlier and more accurate diagnosis of AD, providing the opportunity to intervene earlier in the disease process and to improve outcomes. The known hallmarks of Alzheimer's disease include amyloid-β plaques and neurofibrillary tau tangles. It is now clear that an imbalance between production and clearance of the amyloid beta protein and related Aβ peptides, especially Aβ42, is a very early, initiating factor in Alzheimer's disease (AD) pathogenesis, leading to aggregates of hyperphosphorylation and misfolded tau protein, inflammation, and neurodegeneration. In this article, we review how the AD diagnostic process has been transformed in recent decades by our ability to measure these various elements of the pathological cascade through the use of imaging and fluid biomarkers. The more recently developed plasma biomarkers, especially phosphorylated-tau217 (p-tau217), have utility for screening and diagnosis of the earliest stages of AD. These biomarkers can also be used to measure target engagement by disease-modifying therapies and the response to treatment.},
}

@article {pmid38611464,
year = {2024},
author = {Morocho, V and Benitez, Á and Carrión, B and Cartuche, L},
title = {Novel Study on Chemical Characterization and Antimicrobial, Antioxidant, and Anticholinesterase Activity of Essential Oil from Ecuadorian Bryophyte Syzygiella rubricaulis (Nees) Stephani.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {7},
pages = {},
pmid = {38611464},
issn = {2223-7747},
abstract = {Our research focuses on exploring the chemical composition and some biological properties of the essential oil derived from Syzygiella rubricaulis (Nees) Stephani, a bryophyte species. To conduct a comprehensive analysis, we utilized a DB5MS capillary column along with gas chromatography coupled to mass spectrometry (GC-MS) and flame ionization (GC-FID). The qualitative and quantitative examination revealed the presence of 50 compounds, with hydrocarbon sesquiterpenes (48.35%) and oxygenated sesquiterpenes (46.89%) being the predominant constituents. Noteworthy compounds identified include bicyclogermacrene (12.004%), cedranone <5-> (9.034%), spathulenol (6.835%), viridiflorol (6.334%), silphiperfol-5,7(14)-diene (6.216%), biotol <β-> (6.075%), guaiol (4.607%), viridiflorene (4.65%), and α-guaienol (3.883%). Furthermore, we assessed the antimicrobial, antioxidant, and anticholinesterase activity of the essential oil, revealing a compelling inhibitory effect against acetylcholinesterase (AChE) with an IC50 value of 26.75 ± 1.03 µg/mL and a moderate antimicrobial (MIC 500 µg/mL, Enterococcus faecium, Lysteria monocytogenes) and antioxidant effect (ABTS: SC50 343.38 and DPPH 2650.23 µg/mL). These findings suggest the potential therapeutic application of the bryophyte essential oil in the treatment of Alzheimer's disease due to its potent anticholinesterase properties.},
}

@article {pmid38610807,
year = {2024},
author = {Jiménez-Palomares, M and Garrido-Ardila, EM and Chávez-Bravo, E and Torres-Piles, ST and González-Sánchez, B and Rodríguez-Mansilla, MJ and De Toro-García, Á and Rodríguez-Mansilla, J},
title = {Benefits of Music Therapy in the Cognitive Impairments of Alzheimer's-Type Dementia: A Systematic Review.},
journal = {Journal of clinical medicine},
volume = {13},
number = {7},
pages = {},
pmid = {38610807},
issn = {2077-0383},
abstract = {Background/Objective: Alzheimer's disease is a condition that can cause memory, thinking, and behaviour impairments. This type of dementia affects approximately 50 million people globally. Currently, there is no remedy for this disease, but there are different treatment approaches, both pharmacological and non-pharmacological, that try to alleviate the symptoms. The remarkable fact about Alzheimer's response to music is that musical abilities can be preserved even though language could be lost. The objective of this systematic review is to assess the benefits of music therapy on cognitive impairments in older adults with Alzheimer's disease. Methods: This is a systematic review carried out following the PRISMA guidelines. The literature searches were conducted in the following databases: PubMed, SCOPUS, Cochrane Library, and Dialnet. The inclusion criteria established were as follows: randomised controlled studies and clinical trials published in English and Spanish from 2010 to 2024, patients diagnosed with dementia of the Alzheimer's type, aged 65 years or older, who had participated in music interventions and had cognitive changes. Results: Eleven studies were included in this review. They showed that music therapy interventions mainly improved memory, language, and orientation. The results of a methodological quality analysis showed that six of the articles had good methodological quality and four had excellent methodological quality. Conclusions: The results of this review suggest that treatment with music therapy improves cognitive impairments in patients with Alzheimer's disease. In addition, we can be sure that music creates a link between the patient and the specialist.},
}

@article {pmid38610012,
year = {2024},
author = {Liu, X and Shen, L and Wan, M and Xie, H and Wang, Z},
title = {Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles.},
journal = {Journal of nanobiotechnology},
volume = {22},
number = {1},
pages = {170},
pmid = {38610012},
issn = {1477-3155},
support = {82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 2020YFC2008500//National Key R&D Program of China/ ; },
mesh = {Humans ; Prospective Studies ; *Extracellular Vesicles ; *Exosomes ; *Parkinson Disease ; *Alzheimer Disease ; },
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies. Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: "neurodegenerative disease" OR "Alzheimer's disease" OR "Parkinson's disease" OR "Amyotrophic lateral sclerosis" AND "extracellular vesicles" OR "exosomes" OR "outer membrane vesicles" AND "drug delivery systems" AND "blood-brain barrier". MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.},
}

Humans
Prospective Studies
*Extracellular Vesicles
*Exosomes
*Parkinson Disease
*Alzheimer Disease

@article {pmid38609644,
year = {2024},
author = {Khalil, M and Teunissen, CE and Lehmann, S and Otto, M and Piehl, F and Ziemssen, T and Bittner, S and Sormani, MP and Gattringer, T and Abu-Rumeileh, S and Thebault, S and Abdelhak, A and Green, A and Benkert, P and Kappos, L and Comabella, M and Tumani, H and Freedman, MS and Petzold, A and Blennow, K and Zetterberg, H and Leppert, D and Kuhle, J},
title = {Neurofilaments as biomarkers in neurological disorders - towards clinical application.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {38609644},
issn = {1759-4766},
abstract = {Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.},
}

@article {pmid38609388,
year = {2024},
author = {Huang, X and Qi, J and Su, Y and Zhou, Y and Wang, Q and Huang, T and Xue, D and Zeng, Y and Verkhratsky, A and Zhou, B and Chen, H and Yi, C},
title = {Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease.},
journal = {Cell death & disease},
volume = {15},
number = {4},
pages = {258},
pmid = {38609388},
issn = {2041-4889},
support = {32170980//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82201707//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82200562//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82200179//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Animals ; Mice ; *Blood-Brain Barrier ; *Alzheimer Disease/genetics ; beta Catenin ; Endothelial Cells ; Brain ; Amyloid beta-Peptides ; },
abstract = {The impairment of the blood-brain barrier (BBB) has been increasingly recognised as a critical element in the early pathogenesis of Alzheimer's disease (AD), prompting a focus on brain endothelial cells (BECs), which serve as the primary constituents of the BBB. Death receptor 6 (DR6) is highly expressed in brain vasculature and acts downstream of the Wnt/β-catenin pathway to promote BBB formation during development. Here, we found that brain endothelial DR6 levels were significantly reduced in a murine model of AD (APPswe/PS1dE9 mice) at the onset of amyloid-β (Aβ) accumulation. Toxic Aβ25-35 oligomer treatment recapitulated the reduced DR6 in cultured BECs. We further showed that suppressing DR6 resulted in BBB malfunction in the presence of Aβ25-35 oligomers. In contrast, overexpressing DR6 increased the level of BBB functional proteins through the activation of the Wnt/β-catenin and JNK pathways. More importantly, DR6 overexpression in BECs was sufficient to rescue BBB dysfunction in vitro. In conclusion, our findings provide new insight into the role of endothelial DR6 in AD pathogenesis, highlighting its potential as a therapeutic target to tackle BBB dysfunction in early-stage AD progression.},
}

Animals
Mice
*Blood-Brain Barrier
*Alzheimer Disease/genetics
beta Catenin
Endothelial Cells
Brain
Amyloid beta-Peptides

@article {pmid38609032,
year = {2024},
author = {Han, L and Chen, W and Li, J and Zhao, Y and Zong, Y and He, Z and Du, R},
title = {Palmatine improves cognitive dysfunction in Alzheimer's disease model rats through autophagy pathway and regulation of gut microbiota.},
journal = {Brain research},
volume = {1835},
number = {},
pages = {148932},
doi = {10.1016/j.brainres.2024.148932},
pmid = {38609032},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a primary degenerative encephalopathy that first appeared as a decline in memory and learning skills. Over time, the condition's severity grew. Palmatine (Pal) alleviates Alzheimer's disease symptoms, which has neuroprotective benefits. Numerous investigations have demonstrated a close relationship among AD and gut structure changes. The aim of the research was investigating whether the improvement of Pal on AD is linked to regulating gut flora and autophagy. First, we used Aβ1-40 to induce apoptosis in HT22 cells. After Pal treatment, apoptosis can be improved. Then, We used bilateral intracranial hippocampal injection of Aβ1-40 for establishing the AD model, after treatment with Pal, the morris water maze experiment and eight-arm maze test demonstrated that Pal enhanced the AD rats' capacity for learning and memory, HE staining illustrated that Pal improved the morphological abnormalities of brain cells and gut tissue damage. Pal reduced the death of hippocampus neurons, as shown by Nissl staining. Pal substantially reduced Tau hyperphosphorylation and Aβ accumulation in the brain, according to immunohistochemical labelling. Pal improved the expression of LC3, Beclin 1, AMPK, and suppressed the expression of mTOR and P62, as validated by RT-qPCR and immunofluorescence labelling. This suggests that Pal's treatment of AD may be associated with the control of the AMPK/mTOR autophagy signalling system. 16S rRNA sequencing and short-chain fatty acids (SCFAs) content detection analysis illustrated that Pal has the potential to enhance the content of SCFAs, reverse the alterations in gut microorganisms. It has been showed by the study that Pal could improve AD by activating autophagy signaling pathway and improving gut barrier changes.},
}

@article {pmid38608464,
year = {2024},
author = {Wei, Z and Dong, X and Sun, Y},
title = {Quercetin-derived red emission carbon dots: A multifunctional theranostic nano-agent against Alzheimer's β-amyloid fibrillogenesis.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {238},
number = {},
pages = {113907},
doi = {10.1016/j.colsurfb.2024.113907},
pmid = {38608464},
issn = {1873-4367},
abstract = {Multifunctional agents with therapeutic and diagnostic capabilities are imperative to the prevention of Alzheimer's disease (AD), which is considered due to abnormal aggregation and deposition of β-amyloid protein (Aβ) as well as oxidative stress. Herein, quercetin (Que)- and p-phenylenediamine (p-PD)-derived red emission carbon dots (CDs) synthesized via a one-step hydrothermal method were designed as a novel theranostic nano-agent for the multi-target treatment of AD. R-CD-75 with an optimized composition exhibited significant inhibition of Aβ aggregation and rapid depolymerization of mature Aβ fibrils (<4 h) at micromolar concentrations (2 and 5 μg/mL, respectively). Moreover, R-CD-75 potently scavenged reactive oxygen species and showed turned-on red fluorescence imaging of Aβ plaques both in vitro and in vivo. In vitro assays proved that R-CD-75 significantly mitigated the Aβ-induced cytotoxicity and enhanced the cultured cell viability from 74.9 % to 98.0 %, while in vivo studies demonstrated that R-CD-75 prolonged the lifespan of AD nematodes by over 50 % (from 13 to 20 d). Compared to the precursors Que and p-PD, R-CD-75 inherited some of their structures and functional groups, such as aromatic structures, phenolic hydroxyl and amino groups, which were considered to interact with Aβ species through hydrogen bonding, electrostatic interactions, hydrophobic interactions, and π-π stacking, thus contributing to its effectiveness in its theranostic functions. This research has opened a new avenue to the development of potent theranostic agents by designing novel carbon dots.},
}

@article {pmid38608202,
year = {2024},
author = {Shamim, T and Asif, HM and Ejaz, SA and Hussain, Z and Wani, TA and Sumreen, L and Abdullah, M and Ahmed, Z and Iqbal, J and Kim, SJ and Shah, MK},
title = {Investigations of Limeum indicum Plant for Diabetes Mellitus and Alzheimer's disease Dual Therapy: Phytochemical, GC-MS Chemical Profiling, Enzyme Inhibition, Molecular Docking and In-vivo Studies.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e202301858},
doi = {10.1002/cbdv.202301858},
pmid = {38608202},
issn = {1612-1880},
abstract = {Limeum indicum has been widely utilized in traditional medicine but no experimental work has been done on this herb. The primary objective of this study was to conduct a phytochemical analysis and assess the multifunctional capabilities of aforementioned plant in dual therapy for Alzheimer's disease (AD) and Type 2 diabetes (T2D). The phytochemical screening of ethanol, methanol extract, and their derived fractions of Limeum indicum was conducted using GC-MS, HPLC, UV-analysis and FTIR. The antioxidant capacity was evaluated by DPPH method. The inhibitory potential of the extracts/fractions against α-, β-glucosidase acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoaminine oxidases (MAO-A & B) was evaluated. Results revealed that acetonitrile fraction has highest inhibitory potential against α-glucosidase (IC50=68.47±0.05µg/mL), methanol extract against β-glucosidase (IC50=91.12±0.07µg/mL), ethyl acetate fraction against AChE (IC50=59.0±0.02 µg/mL), ethanol extract against BChE (28.41±0.01µg/mL), n-hexane fraction against MAO-A (IC50=150.5±0.31µg/mL) and methanol extract for MAO-B (IC50=75.95±0.13µg/mL). The docking analysis of extracts\fractions suggested the best binding scores within the active pocket of the respective enzymes. During the in-vivo investigation, ethanol extract produced hypoglycemic effect (134.52±2.79 and 119.38±1.40 mg/dl) after 21 days treatment at dose level of 250 and 500 mg/Kg. Histopathological findings further supported the in-vivo studies.},
}

@article {pmid38608178,
year = {2024},
author = {Nie, H and Wang, X and Luo, Y and Kong, F and Mu, G and Wu, X},
title = {Mechanism Explanation on Improved Cognitive Ability of D-Gal Inducing Aged Mice Model by Lactiplantibacillus plantarum MWFLp-182 via the Microbiota-Gut-Brain Axis.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.3c09675},
pmid = {38608178},
issn = {1520-5118},
abstract = {Gut microbiota can influence cognitive ability via the gut-brain axis. Lactiplantibacillus plantarum MWFLp-182 (L. plantarum MWFLp-182) was obtained from feces of long-living individuals and could exert marked antioxidant ability. Interestingly, this strain reduced the D-galactose-induced impaired cognitive ability in BALB/c mice. To comprehensively elucidate the underlying mechanism, we evaluated the colonization, antioxidant, and anti-inflammatory activities of L. plantarum MWFLp-182, along with the expression of potential genes associated with cognitive ability influenced and gut microbiota. L. plantarum MWFLp-182 enhanced the expression of anti-inflammatory cytokines, reduced the expression of proinflammatory cytokines, and increased tight junction protein expression in the colon. Moreover, L. plantarum MWFLp-182 could modify the gut microbiota. Notably, treatment with L. plantarum MWFLp-182 upregulated the expression of postsynaptic density protein-95, nuclear factor erythroid 2-related factor, nerve growth factor, superoxide dismutase, and brain-derived neurotrophic factor/neuronal nuclei, while downregulating the expression of bcl-2-associated X and malondialdehyde in the hippocampus and upregulating short-chain fatty acids against D-galactose-induced mouse brain deficits. Accordingly, L. plantarum MWFLp-182 could improve cognitive ability in a D-galactose-inducing mouse model.},
}

@article {pmid38477120,
year = {2024},
author = {Geng, C and Chen, C},
title = {Migraine Association with Alzheimer's Disease Risk: Evidence from the UK Biobank Cohort Study and Mendelian Randomization.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-9},
doi = {10.1017/cjn.2024.35},
pmid = {38477120},
issn = {0317-1671},
abstract = {BACKGROUND: Epidemiological studies on the association between migraine and Alzheimer's disease (AD) risk have yielded inconsistent conclusions. We aimed to characterize the phenotypic and genetic relationships between migraine and AD.

METHODS: To investigate the association between migraine and the risk of AD by analyzing data from a large sample of 404,318 individuals who were initially free from all-cause dementia or cognitive impairment, utilizing the UK Biobank dataset. We employed Cox regression modeling and propensity score matching techniques to examine the relationship between migraine and subsequent occurrences of AD. Additionally, the study utilized Mendelian randomization (MR) analysis to identify the genetic relationship between migraine and the risk of AD.

RESULTS: Migraine patients had a significantly increased risk of developing AD, compared to non-migraine patients (adjusted hazard ratio (HR) = 2.34, 95% confidence interval (CI) = 2.01-0.74, P < 0.001). Moreover, the propensity scores matching analyses found that migraine patients had a significantly higher risk of developing AD compared to non-migraine patients (HR = 1.85, 95%CI = 1,68-2.05, P < 0.001). Additionally, the MR suggested that significant causal effects of migraine on AD risks were observed [odds ratio (OR) = 2.315; 95% confidence interval (CI) = 1.029-5.234; P = 0.002]. Moreover, no evidence supported the causal effects of AD on migraine (OR = 1.000; 95%CI = 0.999-1.006; P = 0.971).

CONCLUSION: The present study concludes that migraine patients, compared to a matched control group, exhibit an increased risk of developing AD. Moreover, migraine patients exhibit an increased predisposition of genetic susceptibility to AD. These findings hold significant clinical value for early intervention and treatment of migraines to reduce the risk of AD.},
}

@article {pmid38608086,
year = {2024},
author = {Tong, T and Cheng, B and Tie, S and Ouyang, D and Cao, J},
title = {Exploring Acori Tatarinowii Rhizoma and Polygalae Radix in Alzheimer's: Network pharmacology and molecular docking analysis.},
journal = {Medicine},
volume = {103},
number = {15},
pages = {e37740},
doi = {10.1097/MD.0000000000037740},
pmid = {38608086},
issn = {1536-5964},
abstract = {Explore Acori Tatarinowii Rhizoma (ATR) and Polygalae Radix (PR) mechanisms in Alzheimer's disease (AD) treatment through network pharmacology. ATR-PR was investigated in the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, Batman, and Traditional Chinese Medicines Integrated Database (TCMID) to gather information on its chemical components and target proteins. Target genes associated with AD were retrieved from the GeneCards and National Center for Biotechnology Information (NCBI) databases. The integration of these datasets with potential targets facilitated the construction of an AD and ATR-PR protein-protein interaction (PPI) network using the STRING database. The resulting network identified the core active ingredients and main targets of ATR-PR in AD treatment. Cluster analysis of the PPI network was performed using Cytoscape 3.7.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Metascape database. Molecular docking simulations revealed potential interactions between the main active ingredients and core targets. Our analysis identified 8 putative components and 455 targets of ATR-PR. We systematically searched for 1306 genes associated with AD, conducted Venn diagram analysis resulting in 156 common targets, and constructed a PPI network with 57 key targets. GO functional analysis highlighted the primary biological processes associated with oxidative stress. KEGG pathway enrichment analysis revealed the involvement of 64 signaling pathways, with the PI3K/Akt signaling pathway playing a key role. Molecular docking analysis indicated a high affinity between the potential targets of ATR-PR and the main compounds of AD. This study sheds light on the complex network of interactions involving ATR-PR in the context of AD. The identified targets, pathways, and interactions provide a foundation for understanding the potential therapeutic mechanisms. The involvement of oxidative stress-related processes and the crucial role of the PI3K/Akt signaling pathway suggest avenues for targeted therapeutic interventions in Alzheimer's disease treatment. Our proposition of the combined use of ATR-PR has emerged as a potential treatment strategy for AD, supported by a network pharmacology approach. This framework provides a robust foundation for future clinical applications and experimental research in the pursuit of effective Alzheimer's disease treatments.},
}

@article {pmid38607755,
year = {2024},
author = {Sachdeva, P and Narayanan, KB and Sinha, JK and Gupta, S and Ghosh, S and Singh, KK and Bhaskar, R and Almutary, AG and Zothantluanga, JH and Kotta, KK and Nelson, VK and Paiva-Santos, AC and Abomughaid, MM and Kamal, M and Iqbal, D and ALHarbi, MH and ALMutairi, AA and Dewanjee, S and Nuli, MV and Vippamakula, S and Jha, SK and Ojha, S and Jha, NK},
title = {Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-231181},
pmid = {38607755},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-β plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3β, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.},
}

@article {pmid38607082,
year = {2024},
author = {Zadrozny, M and Drapich, P and Gasiorowska-Bien, A and Niewiadomski, W and Harrington, CR and Wischik, CM and Riedel, G and Niewiadomska, G},
title = {Neuroprotection of Cholinergic Neurons with a Tau Aggregation Inhibitor and Rivastigmine in an Alzheimer's-like Tauopathy Mouse Model.},
journal = {Cells},
volume = {13},
number = {7},
pages = {},
pmid = {38607082},
issn = {2073-4409},
support = {PAR1763 and NCN 2014/15/B/NZ4/05041, respectively//WisTa Laboratories Ltd., an affiliate of TauRx Therapeutics Ltd., Singapore and National Science Centre Poland/ ; },
abstract = {Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer's disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. However, its efficacy was diminished in patients already receiving approved acetylcholinesterase inhibitors. In this study, we ask whether this negative interaction can also be mimicked in experimental tau models of AD and whether the underlying mechanism can be understood. From a previous age profiling study, 6-month-old line 1 (L1) tau transgenic mice were characterized by a severe reduction in several cholinergic markers. We therefore assessed whether long-term pre-exposure with the acetylcholinesterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor HMTM can reverse cholinergic deficits in L1. Rivastigmine and HMTM, and combinations of the two compounds were administered orally for 11 weeks to both L1 and wild-type mice. The brains were sectioned with a focus on the basal forebrain, motor cortex and hippocampus. Immunohistochemical staining and quantification of choline acetyltransferase (ChAT), tyrosine kinase A (TrkA)-positive neurons and relative optical intensity (ROI) for vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) reactivity confirmed reversal of the diminished cholinergic phenotype of interneurons (nucleus accumbens, striatum) and projection neurons (medial septum, nucleus basalis magnocellularis) by HMTM, to a greater extent than by rivastigmine alone in L1 mice. Combined administration did not yield additivity but, in most proxies, led to antagonistic effects in which rivastigmine decreased the benefits shown with HMTM alone. Local markers (VAChT and AChE) in target structures of the basal forebrain, motor cortex and hippocampal CA3 seemed to be normalized by HMTM, but not by rivastigmine or the combination of both drugs. HMTM, which was developed as a tau aggregation inhibitor, strongly decreased the tau load in L1 mice, however, not in combination with rivastigmine. Taken together, these data confirm a cholinergic phenotype in L1 tau transgenic mice that resembles the deficits observed in AD patients. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets.},
}

@article {pmid38606366,
year = {2024},
author = {Shah, J and Siddiquee, MMR and Su, Y and Wu, T and Li, B},
title = {Ordinal Classification with Distance Regularization for Robust Brain Age Prediction.},
journal = {IEEE Winter Conference on Applications of Computer Vision. IEEE Winter Conference on Applications of Computer Vision},
volume = {2024},
number = {},
pages = {7867-7876},
pmid = {38606366},
issn = {2472-6737},
support = {P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; RF1 AG073424/AG/NIA NIH HHS/United States ; },
abstract = {Age is one of the major known risk factors for Alzheimer's Disease (AD). Detecting AD early is crucial for effective treatment and preventing irreversible brain damage. Brain age, a measure derived from brain imaging reflecting structural changes due to aging, may have the potential to identify AD onset, assess disease risk, and plan targeted interventions. Deep learning-based regression techniques to predict brain age from magnetic resonance imaging (MRI) scans have shown great accuracy recently. However, these methods are subject to an inherent regression to the mean effect, which causes a systematic bias resulting in an overestimation of brain age in young subjects and underestimation in old subjects. This weakens the reliability of predicted brain age as a valid biomarker for downstream clinical applications. Here, we reformulate the brain age prediction task from regression to classification to address the issue of systematic bias. Recognizing the importance of preserving ordinal information from ages to understand aging trajectory and monitor aging longitudinally, we propose a novel ORdinal Distance Encoded Regularization (ORDER) loss that incorporates the order of age labels, enhancing the model's ability to capture age-related patterns. Extensive experiments and ablation studies demonstrate that this framework reduces systematic bias, outperforms state-of-art methods by statistically significant margins, and can better capture subtle differences between clinical groups in an independent AD dataset. Our implementation is publicly available at https://github.com/jaygshah/Robust-Brain-Age-Prediction.},
}

@article {pmid38606170,
year = {2024},
author = {Qi, Y and Wang, L and Wang, N and Wang, S and Zhu, X and Zhao, T and Jiang, Q},
title = {A comprehensive review of the botany, phytochemistry, pharmacology, and toxicology of Murrayae Folium et Cacumen.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1337161},
pmid = {38606170},
issn = {1663-9812},
abstract = {Ethnopharmacological relevance: Murrayae Folium et Cacumen (MFC) is a plant considered to be a traditional Chinese medicine with culinary value as well. The dry leaves and twigs of Murraya paniculata and M. exotica are used to treat stomach aches, rheumatism, toothaches, swelling, and insect and snake bites. They are also used to prepare spicy chicken dishes. Aim of the review: This review comprehensively summarizes the available information on the botanical characterization, phytochemistry, pharmacological activities, pharmacodynamics, pharmacokinetics, and toxicity of MFC. Methods: Relevant scientific literature up to August 2023 was included in the study. Chinese and English studies on MFC were collected from databases, including PubMed, Elsevier, Web of Science, Springer, Science Direct, Wiley, ACS, and CNKI (Chinese). Doctoral and Master's dissertations were also included. Results: In total, 720 compounds have been identified and reported in the literature, including flavonoids, coumarins, alkaloids, sterols, phenylpropenols, organic acids, spirocyclopentenones, and volatile oils. Flavonoids and coumarins are the two most important bioactive compounds responsible for these pharmacological activities. MFC has anti-inflammatory, anti-bacterial, anti-microbial, anti-diabetic, anti-tumor, anti-oxidant, anti-depressant, potential anti-Alzheimer's disease, chondroprotective, and analgesic properties. The pharmacological effects include interrupting the STAT3/NF-κB/COX-2 and EGFR signaling pathways, downregulating EpCAM expression, inhibiting NF-κB and ERK signals, inhibiting the EP/cAMP/PKA signaling pathway and miR-29a/Wnt/β-catenin signaling activity, and upregulating Foxo3a expression. Conclusion: This review demonstrates that the chemical constituents, pharmacological activities, pharmacodynamics, pharmacokinetics, and toxicity of MFC support its use in traditional Chinese botanical medicines. MFC contains a wide range of chemical compounds. Flavonoids and coumarins promote strong pharmacological activity and, are low-toxicity natural phytomedicines that are widely used in medicine, food, ornamentation, and cosmetics, making MFC a promising compound for development and use in the treatment of several medical conditions.},
}

@article {pmid38606018,
year = {2024},
author = {Wang, ZL and Pang, SJ and Zhang, KW and Li, PY and Li, PG and Yang, C},
title = {Dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aβ pathology.},
journal = {Frontiers in nutrition},
volume = {11},
number = {},
pages = {1367086},
pmid = {38606018},
issn = {2296-861X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disorder with no effective interventions for curing or modifying its progression. However, emerging research suggests that vitamin A in the diet may play a role in both the prevention and treatment of AD, although the exact mechanisms are not fully understood.

OBJECTIVES: This study aims to investigate the dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aβ pathology shedding light on its potential as a dietary intervention for AD prevention and treatment.

METHODS: The APP/PS1-AD mouse model was employed and divided into three dietary groups: vitamin A-deficient (VAD), normal vitamin A (VAN), and vitamin A-supplemented (VAS) for a 12-week study. Neurobehavioral functions were assessed using the Morris Water Maze Test (MWM). Enzyme-linked immunosorbent assay (ELISA) was used to quantify levels of Diamine Oxidase (DAO), D-lactate, IL-6, IL-1β, and TNF-a cytokines. Serum vitamin A levels were analyzed via LC-MS/MS analysis. Immunohistochemical analysis and morphometry were performed to evaluate the deposition of Aβ in brain tissue. The gut microbiota of APP/PS1 mice was analyzed using 16S rRNA sequencing analysis. Additionally, transcriptomic analysis was conducted on intestinal tissue from APP/PS1 mice.

RESULTS: No significant changes in food intake and body weight were observed among the groups. However, the VAD and VAS groups showed reduced food intake compared to the VAN group at various time points. In terms of cognitive function, the VAN group performed better in the Morris Water Maze Test, indicating superior learning and memory abilities. The VAD and VAS groups exhibited impaired performance, with the VAS group performing relatively better than the VAD group. Serum vitamin A concentrations differed significantly among the groups, with the VAS group having the highest concentration. Aβ levels were significantly higher in the VAD group compared to both the VAN and VAS groups. Microbial analysis revealed that the VAS and VAN groups had higher microbial diversity than the VAD group, with specific taxa characterizing each group. The VAN group was characterized by taxa such as Actinohacteriota and Desulfovibrionaceae, while the VAD group was characterized by Parabacteroides and Tannerellaceae. The VAS group showed similarities with both VAN and VAD groups, with taxa like Desulfobacterota and Desulfovibrionaceae being present. The VAD vs. VAS, VAD vs. VAN, and VAS vs. VAN comparisons identified 571, 313, and 243 differentially expressed genes, respectively, which associated with cellular and metabolic processes, and pathway analysis revealed enrichment in pathways related to chemical carcinogenesis, drug metabolism, glutathione metabolism, and immune-related processes. The VAD group exhibited higher levels of D-lactate, diamine oxidase, and inflammatory cytokines (TNF-a, IL-1β, IL-6) compared to the VAN and VAS groups.

CONCLUSION: Dietary vitamin A supplementation modulates the gut microbiota, intestinal permeability, inflammatory factors, and Aβ protein formation, offering insights into the pathogenesis of AD and potential therapeutic avenues for further exploration. This research highlights the intricate interplay between diet, gut microbiota, and neurodegenerative processes, emphasizing the importance of dietary interventions in managing AD-related pathologies.},
}