@article {pmid38680427,
year = {2023},
author = {Tandon, R and Kirkpatrick, A and Mitchell, CS},
title = {sEBM: Scaling Event Based Models to Predict Disease Progression via Implicit Biomarker Selection and Clustering.},
journal = {Information processing in medical imaging : proceedings of the ... conference},
volume = {13939},
number = {},
pages = {208-221},
doi = {10.1007/978-3-031-34048-2_17},
pmid = {38680427},
issn = {1011-2499},
abstract = {The Event Based Model (EBM) is a probabilistic generative model to explore biomarker changes occurring as a disease progresses. Disease progression is hypothesized to occur through a sequence of biomarker dysregulation "events". The EBM estimates the biomarker dysregulation event sequence. It computes the data likelihood for a given dysregulation sequence, and subsequently evaluates the posterior distribution on the dysregulation sequence. Since the posterior distribution is intractable, Markov Chain Monte-Carlo is employed to generate samples under the posterior distribution. However, the set of possible sequences increases as N! where N is the number of biomarkers (data dimension) and quickly becomes prohibitively large for effective sampling via MCMC. This work proposes the "scaled EBM" (sEBM) to enable event based modeling on large biomarker sets (e.g. high-dimensional data). First, sEBM implicitly selects a subset of biomarkers useful for modeling disease progression and infers the event sequence only for that subset. Second, sEBM clusters biomarkers with similar positions in the event sequence and only orders the "clusters", with each successive cluster corresponding to the next stage in disease progression. These two modifications used to construct the sEBM method provably reduces the possible space of event sequences by multiple orders of magnitude. The novel modifications are supported by theory and experiments on synthetic and real clinical data provides validation for sEBM to work in higher dimensional settings. Results on synthetic data with known ground truth shows that sEBM outperforms previous EBM variants as data dimensions increase. sEBM was successfully implemented with up to 300 biomarkers, which is a 6-fold increase over previous EBM applications. A real-world clinical application of sEBM is performed using 119 neuroimaging markers from publicly available Alzheimer's Disease Neuroimaging Initiative (ADNI) data to stratify subjects into 6 stages of disease progression. Subjects included cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's Disease (AD). sEBM stage is differentiated for the 3 groups (χ2p-value<4.6e-32). Increased sEBM stage is a strong predictor of conversion risk to AD (p-value<2.3e-14) for MCI subjects, as verified with a Cox proportional-hazards model adjusted for age, sex, education and APOE4 status. Like EBM, sEBM does not rely on apriori defined diagnostic labels and only uses cross-sectional data.},
}

@article {pmid38680351,
year = {2024},
author = {Singh, A and Verma, A and Bhardwaj, B and Saraf, P and Kumar, H and Jain, N and Waiker, DK and Gajendra, TA and Krishnamurthy, S and Shrivastava, SK},
title = {Structure-Guided Design, Synthesis, and Biological Evaluation of Peripheral Anionic Site Selective and Brain Permeable Novel Oxadiazole-Piperazine Conjugates against Alzheimer's Disease with Antioxidant Potential.},
journal = {ACS omega},
volume = {9},
number = {16},
pages = {18169-18182},
doi = {10.1021/acsomega.3c10276},
pmid = {38680351},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound 5AD comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC50 = 0.103 ± 0.0172 μM, hBChE, IC50 ≥ 10 μM, and hBACE-1, IC50 = 1.342 ± 0.078 μM). Compound 5AD showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound 5AD revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood-brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, 5AD also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound 5AD has shown significant improvement in learning and memory (p < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound 5AD, there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound 5AD could be regarded as a lead compound and further be explored in the treatment of AD.},
}

@article {pmid38680184,
year = {2024},
author = {Mustafin, RN and Khusnutdinova, EK},
title = {Involvement of transposable elements in Alzheimer's disease pathogenesis.},
journal = {Vavilovskii zhurnal genetiki i selektsii},
volume = {28},
number = {2},
pages = {228-238},
doi = {10.18699/vjgb-24-27},
pmid = {38680184},
issn = {2500-0462},
abstract = {Alzheimer's disease affects an average of 5 % of the population with a significant increase in prevalence with age, suggesting that the same mechanisms that underlie aging may influence this pathology. Investigation of these mechanisms is promising for effective methods of treatment and prevention of the disease. Possible participants in these mechanisms are transposons, which serve as drivers of epigenetic regulation, since they form species-specific distributions of non-coding RNA genes in genomes in evolution. Study of miRNA involvement in Alzheimer's disease pathogenesis is relevant, since the associations of protein-coding genes (APOE4, ABCA7, BIN1, CLU, CR1, PICALM, TREM2) with the disease revealed as a result of GWAS make it difficult to explain its complex pathogenesis. Specific expression changes of many genes were found in different brain parts of Alzheimer's patients, which may be due to global regulatory changes under the influence of transposons. Experimental and clinical studies have shown pathological activation of retroelements in Alzheimer's disease. Our analysis of scientific literature in accordance with MDTE DB revealed 28 miRNAs derived from transposons (17 from LINE, 5 from SINE, 4 from HERV, 2 from DNA transposons), the expression of which specifically changes in this disease (decreases in 17 and increases in 11 microRNA). Expression of 13 out of 28 miRNAs (miR-151a, -192, -211, -28, -31, -320c, -335, -340, -378a, -511, -576, -708, -885) also changes with aging and cancer development, which indicates the presence of possible common pathogenetic mechanisms. Most of these miRNAs originated from LINE retroelements, the pathological activation of which is associated with aging, carcinogenesis, and Alzheimer's disease, which supports the hypothesis that these three processes are based on the primary dysregulation of transposons that serve as drivers of epigenetic regulation of gene expression in ontogeny.},
}

@article {pmid38680104,
year = {2024},
author = {Farid, M and Marzouk, M and Ivanova, V and Nedialkov, P and El Shabrawy, M and Kawashty, S and Sakr, M and Hussein, S and Trendafilova, A},
title = {Metabolomic Profiling and DNA-Fingerprinting of Newly Recorded White-Flowered Populations of Salvia lanigera Poir. in Egypt.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e202400619},
doi = {10.1002/cbdv.202400619},
pmid = {38680104},
issn = {1612-1880},
abstract = {Salvia lanigera Poir. is a small herbaceous perennial species with violet flowers that grows in low-altitude deserts, and sandy loam. During the collection of S. lanigera, unusual populations with white flowers were found. Therefore, the two populations (violet- and white-flowered) were subjected to comparative investigations, including DNA fingerprinting, chemical composition, and biological evaluation. The two populations showed DNA variations, with 6.66% polymorphism in ISSR and 25% in SCoT markers. GC/MS and UHPLC/HRMS of aqueous methanol extracts, led to the tentative identification of 43 and 50 compounds in both populations. In addition, the structures of nine compounds, including four first-reported compounds in the species, were confirmed by NMR. Furthermore, the total extracts exhibited weak radical scavenging activity against DPPH and a lower inhibitory effect towards acetylcholinesterase. In conclusion, the obtained data suggested that the white-colored flower could be an additional important character record for the Egyptian S. lanigera.},
}

@article {pmid38680097,
year = {2024},
author = {Olesen, KKW and Thrane, PG and Gyldenkerne, C and Thomsen, RW and Mortensen, JK and Kristensen, SD and Maeng, M},
title = {Diabetes and Coronary Artery Disease as Risk Factors for Dementia.},
journal = {European journal of preventive cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurjpc/zwae153},
pmid = {38680097},
issn = {2047-4881},
abstract = {AIM: Diabetes is associated with increased risk of dementia, but it is still debated to which degree this risk depends on the presence of atherosclerotic cardiovascular disease. We hypothesized that patients with diabetes and co-existing coronary artery disease (CAD), as a marker of systemic atherosclerotic cardiovascular disease, have substantially higher risk of developing dementia.

METHODS: Patients ≥65 years, who underwent coronary angiography were stratified by diabetes and CAD. Outcomes were all-cause dementia, Alzheimer's dementia, and vascular dementia. We estimated adjusted hazard ratios (aHRs) using patients with neither diabetes nor CAD as a reference.

RESULTS: A total of 103,859 patients were included. Of these, 23,189 (22%) had neither diabetes nor CAD, 3,876 (4%) had diabetes, 61,020 (59%) had CAD, and 15,774 (15%) had diabetes and CAD. During a median follow-up of 6.3 years, 5,592 (5.5%) patients were diagnosed with all-cause dementia. Patients with diabetes and CAD had the highest hazard rate of all-cause dementia (aHR 1.37, 95% CI 1.24-1.51), including Alzheimer's dementia (aHR 1.41, 95% CI 1.23-1.62) and vascular dementia (aHR 2.03, 95% CI 1.69-2.45). Patients with diabetes alone (aHR 1.14, 95% CI 0.97-1.33) or CAD alone (aHR 1.11, 95% CI 1.03-1.20) had a modestly increased rate of all-cause dementia.

CONCLUSION: The combination of diabetes and CAD is associated with increased rate of dementia, in particular vascular dementia, suggesting that the diabetes-related risk of dementia is partly mediated through concomitant atherosclerotic cardiovascular disease. This underscores the importance of atherosclerotic cardiovascular disease prevention in diabetes patients to reduce cognitive decline.},
}

@article {pmid38679805,
year = {2024},
author = {Kharaghani, A and Tio, ES and Milic, M and Bennett, DA and De Jager, PL and Schneider, JA and Sun, L and Felsky, D},
title = {Association of whole-person eigen-polygenic risk scores with Alzheimer's disease.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddae067},
pmid = {38679805},
issn = {1460-2083},
support = {/CAPMC/CIHR/Canada ; },
abstract = {Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.},
}

@article {pmid38679634,
year = {2024},
author = {Wang, X and Liu, Q and Yu, HT and Xie, JZ and Zhao, JN and Fang, ZT and Qu, M and Zhang, Y and Yang, Y and Wang, JZ},
title = {A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology.},
journal = {Signal transduction and targeted therapy},
volume = {9},
number = {1},
pages = {105},
pmid = {38679634},
issn = {2059-3635},
support = {82230041//National Natural Science Foundation of China (National Science Foundation of China)/ ; 91949205//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31730035//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81721005//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82301624//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Animals ; *Alzheimer Disease/genetics/pathology/metabolism ; Mice ; Humans ; *Mice, Transgenic ; *Isocitrate Dehydrogenase/genetics/metabolism ; PAX6 Transcription Factor/genetics/metabolism ; Feedback, Physiological ; Male ; Female ; },
abstract = {Impaired brain glucose metabolism is an early indicator of Alzheimer's disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3β (IDH3β) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice's brains. Further investigations demonstrated that the knockdown of IDH3β induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3β, the elevated PAX6 in turn inhibited the expression of IDH3β, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3β and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β. Breaking this loop by upregulating IDH3β or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.},
}

Animals
*Alzheimer Disease/genetics/pathology/metabolism
Mice
Humans
*Mice, Transgenic
*Isocitrate Dehydrogenase/genetics/metabolism
PAX6 Transcription Factor/genetics/metabolism
Feedback, Physiological
Male
Female

@article {pmid38679474,
year = {2024},
author = {Sun, F and Wang, J and Meng, L and Zhou, Z and Xu, Y and Yang, M and Li, Y and Jiang, T and Liu, B and Yan, H},
title = {AdipoRon promotes amyloid-β clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer's disease.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.16400},
pmid = {38679474},
issn = {1476-5381},
support = {81500930//National Natural Science Foundation of China/ ; 81901380//National Natural Science Foundation of China/ ; 82101584//National Natural Science Foundation of China/ ; ZR2014HQ014//Natural Science Foundation of Shandong Province/ ; ZR2017BC047//Natural Science Foundation of Shandong Province/ ; ZR2021MH196//Natural Science Foundation of Shandong Province/ ; ZR2021QH139//Natural Science Foundation of Shandong Province/ ; ZR2022QH138//Natural Science Foundation of Shandong Province/ ; },
abstract = {BACKGROUND AND PURPOSE: Amyloid-β (Aβ) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aβ. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aβ and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aβ clearance remain unclear.

EXPERIMENTAL APPROACH: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process.

KEY RESULTS: AdipoRon promotes Aβ clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aβ deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD.

CONCLUSION AND IMPLICATIONS: AdipoRon promotes the clearance of Aβ by enhancing autophagy through the AdipoR1/AMPK-dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.},
}

@article {pmid38679331,
year = {2024},
author = {Duan, P and El Mammeri, N and Hong, M},
title = {Milligram-Scale Assembly and NMR Fingerprint of Tau Fibrils Adopting the Alzheimer's Disease Fold.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {107326},
doi = {10.1016/j.jbc.2024.107326},
pmid = {38679331},
issn = {1083-351X},
abstract = {In the Alzheimer's disease (AD) brain, the microtubule-associated protein tau aggregates into paired helical filaments (PHFs) in which each protofilament has a C-shaped conformation. In vitro assembly of tau fibrils adopting this fold is highly valuable for both fundamental and applied studies of AD without requiring patient-brain extracted fibrils. To date, reported methods for forming AD-fold tau fibrils have been irreproducible and sensitive to subtle variations in fibrillization conditions. Here we describe a route to reproducibly assemble tau fibrils adopting the AD fold on the multi-milligram scale. We investigated the fibrilization conditions of two constructs, and found that a tau (297-407) construct that contains four AD phospho-mimetic glutamate mutations robustly formed the C-shaped conformation. Two- and three-dimensional correlation solid-state NMR spectra show a single predominant set of chemical shifts, indicating a single molecular conformation. Negative-stain electron microscopy and cryoelectron microscopy data confirm that the protofilament formed by 4E-tau (297-407) adopts the C-shaped conformation, which associates into paired, triple and quadruple helical filaments. In comparison, NMR spectra indicate that a previously reported construct, tau (297-391), forms a mixture of a four-layered dimer structure and the C-shaped structure, whose populations are highly sensitive to the environmental conditions. The determination of the NMR chemical shifts of the AD-fold tau opens the possibility for future studies of tau fibril conformations and ligand binding by NMR. The quantitative assembly of tau fibrils adopting the AD fold should facilitate the development of diagnostic and therapeutic compounds that target AD tau.},
}

@article {pmid38679313,
year = {2024},
author = {Nefodova, A and Rudyk, M and Dovhyi, R and Dovbynchuk, T and Dzubenko, N and Tolstanova, G and Skivka, L},
title = {Systemic inflammation in Aβ1-40-induced Alzheimer's disease model: New translational opportunities.},
journal = {Brain research},
volume = {},
number = {},
pages = {148960},
doi = {10.1016/j.brainres.2024.148960},
pmid = {38679313},
issn = {1872-6240},
abstract = {Alzheimer disease (AD) is the most frequent cause of dementia, and the most common neurodegenerative disease, which is characterized by memory impairment, neuronal death, and synaptic loss in the hippocampus. Sporadic late-onset AD, which accounts for over 95 % of disease cases, is a multifactorial pathology with complex etiology and pathogenesis. Nowadays, neuroinflammation is considered the third most important component of AD pathogenesis in addition to amyloid peptide generation and deposition. Neuroinflammation is associated with the impairment of blood-brain barrier and leakage of inflammatory mediators into the periphery with developing systemic inflammatory responses. Systemic inflammation is currently considered one of the therapeutic targets for AD treatment, that necessitates in-depth study of this phenomenon in appropriate non-transgenic animal models. This study was aimed to explore systemic inflammatory manifestations in rats with Aβ1-40-induced AD. The impairment of spatial memory and cognitive flexibility in Aβ1-40-lesioned rats was accompanied by pronounced systemic inflammation, which was confirmed by commonly accepted biomarkers: increased hematological indices of systemic inflammation (NLR, dNLR, LMR, PLR and SII), signs of anemia of inflammation or chronic diseases, and pro-inflammatory polarized activation of circulating phagocytes. In addition, markers of systemic inflammation strongly correlated with disorders of remote cognitive flexibility in Aβ1-40-lesioned rats. These results indicate, that Aβ1-40-induced AD model permits the investigation of specific element of the disease - systemic inflammation in addition to well reproduced neuroinflammation and impairment of spatial memory and cognitive flexibility. It increases translational value of this well-known model.},
}

@article {pmid38679260,
year = {2024},
author = {Yekeler, HB and Guler, E and Beato, PS and Priya, S and Abobakr, FKM and Dogan, M and Uner, B and Kalaskar, DM and Cam, ME},
title = {Design and in vitro evaluation of curcumin-loaded PLGA nanoparticle embedded sodium alginate/gelatin 3D printed scaffolds for Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {131841},
doi = {10.1016/j.ijbiomac.2024.131841},
pmid = {38679260},
issn = {1879-0003},
abstract = {BACKGROUND: Targeted nanoparticles (NPs) are aimed at improving clinical outcomes by enhancing the diagnostic and therapeutic efficacy of drugs in the treatment of Alzheimer's disease (AD).

METHODS: Curcumin (CUR)-loaded poly-lactic-co-glycolic acid (PLGA) NPs (CNPs) were produced to demonstrate a prolonged release and successfully embedded into 3D printed sodium alginate (SA)/gelatin (GEL) scaffolds that can dissolve rapidly sublingually. Characterization and in vitro activity of the NPs and scaffolds were evaluated.

RESULTS: Based on the in vitro drug release studies, 99.6 % of the encapsulated CUR was released in a controlled manner within 18 days for the CNPs. In vitro cell culture studies showed that all samples exhibited cell viability above 84.2 % and no significant cytotoxic effect on SH-SY5Y cells. The samples were analyzed through 2 different pathways by PCR analysis. Real-time PCR results indicated that CNP and CNP-embedded SA/GEL scaffolds (CNPSGS) may show neuroprotective effects by modulating the Wnt/β-catenin pathway. The gene expression level of β-catenin slightly increased compared to the gene expression levels of other proteins and enzymes with these treatments. However, the PI3K/Akt/GSK-3β signaling pathway was regulated at the same time because of the crosstalk between these 2 pathways.

CONCLUSION: CNPSGS might be an effective therapeutic alternative for AD treatment.},
}

@article {pmid38679217,
year = {2024},
author = {Rabanal-Ruiz, Y and Pedrero-Prieto, CM and Sanchez-Rodriguez, L and Flores-Cuadrado, A and Saiz-Sanchez, D and Frontinan-Rubio, J and Ubeda-Banon, I and Duran Prado, M and Martinez-Marcos, A and Peinado, JR},
title = {Differential accumulation of human β-amyloid and tau from enriched extracts in neuronal and endothelial cells.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167204},
doi = {10.1016/j.bbadis.2024.167204},
pmid = {38679217},
issn = {1879-260X},
abstract = {While Aβ and Tau cellular distribution has been largely studied, the comparative internalization and subcellular accumulation of Tau and Aβ isolated from human brain extracts in endothelial and neuronal cells has not yet been unveiled. We have previously demonstrated that controlled enrichment of Aβ from human brain extracts constitutes a valuable tool to monitor cellular internalization in vitro and in vivo. Herein, we establish an alternative method to strongly enrich Aβ and Tau aggregates from human AD brains, which has allowed us to study and compare the cellular internalization, distribution and toxicity of both proteins within brain barrier endothelial (bEnd.3) and neuronal (Neuro2A) cells. Our findings demonstrate the suitability of human enriched brain extracts to monitor the intracellular distribution of human Aβ and Tau, which, once internalized, show dissimilar sorting to different organelles within the cell and differential toxicity, exhibiting higher toxic effects on neuronal cells than on endothelial cells. While tau is strongly concentrated preferentially in mitochondria, Aβ is distributed predominantly within the endolysosomal system in endothelial cells, whereas the endoplasmic reticulum was its preferential location in neurons. Altogether, our findings display a picture of the interactions that human Aβ and Tau might establish in these cells.},
}

@article {pmid38678965,
year = {2024},
author = {Liu, C and Ding, X and Zhao, M and Chen, C and Zhang, X and Zhao, R and Chen, Y and Xie, Y},
title = {Biological effects and mechanism of β-amyloid aggregation inhibition by penetrable recombinant human HspB5-ACD structural domain protein.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {175},
number = {},
pages = {116661},
doi = {10.1016/j.biopha.2024.116661},
pmid = {38678965},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a global medical challenge. Studies have shown that neurotoxicity caused by pathological aggregation of β-amyloid (Aβ) is an important factor leading to AD. Therefore, inhibiting the pathological aggregation of Aβ is the key to treating AD. The recombinant human HspB5-ACD structural domain protein (AHspB5) prepared by our group in the previous period has been shown to have anti-amyloid aggregation effects, but its inability to penetrate biological membranes has limited its development. In this study, we prepared a recombinant fusion protein (T-AHspB5) of TAT and AHspB5. In vitro experiments showed that T-AHspB5 inhibited the formation of Aβ1-42 protofibrils and had the ability to penetrate the blood-brain barrier; in cellular experiments, T-AHspB5 prevented Aβ1-42-induced oxidative stress damage, apoptosis, and inflammatory responses in neuronal cells, and its mechanism of action was related to microglia activation and mitochondria-dependent apoptotic pathway. In animal experiments, T-AHspB5 improved memory and cognitive dysfunction and inhibited pathological changes of AD in APP/PS1 mice. In conclusion, this paper is expected to reveal the intervention mechanism and biological effect of T-AHspB5 on pathological aggregation of Aβ1-42, provide a new pathway for the treatment of AD, and lay the foundation for the future development and application of T-AHspB5.},
}

@article {pmid38678955,
year = {2024},
author = {Sun, C and Dong, S and Chen, W and Li, J and Luo, E and Ji, J},
title = {Berberine alleviates Alzheimer's disease by regulating the gut microenvironment, restoring the gut barrier and brain-gut axis balance.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {129},
number = {},
pages = {155624},
doi = {10.1016/j.phymed.2024.155624},
pmid = {38678955},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Intestinal flora and its metabolism play a significant role in ameliorating central nervous system disorders, including AD, through bidirectional interactions between the gut-brain axis. A naturally occurring alkaloid compound called berberine (BBR) has neuroprotective properties and prevents Aβ-induced microglial activation. Additionally, BBR can suppress the synthesis of Aβ and decrease BACE1 expression. However, it is still unclear if BBR therapy can alleviate AD by changing the gut flora.

PURPOSE: In this study, we examined whether a partial alleviation of AD could be achieved with BBR treatment and the molecular mechanisms involved.

METHODS: We did this by analyzing alterations in Aβ plaques, neurons, and related neuroinflammation-related markers in the brain and the transcriptome of the mouse brain. The relationship between the intestinal flora of 5xFAD model mice and BBR treatment was investigated using high-throughput sequencing analysis of 16S rRNA from mouse feces.

RESULTS: The findings demonstrated that treatment with BBR cleared Aβ plaques, alleviated neuroinflammation, and ameliorated spatial memory dysfunction in AD. BBR significantly alleviated intestinal inflammation, decreased intestinal permeability, and could improve intestinal microbiota composition in 5xFAD mice.},
}

@article {pmid38678735,
year = {2024},
author = {Slattery, DA},
title = {Insights from animal models on insulin signalling disturbances and related diseases in neurological and mental conditions.},
journal = {Neuroscience and biobehavioral reviews},
volume = {161},
number = {},
pages = {105694},
doi = {10.1016/j.neubiorev.2024.105694},
pmid = {38678735},
issn = {1873-7528},
abstract = {There has been a growing awareness of the need for scientific research to focus on somatic and mental comorbidities in recent years due to the emerging evidence showing their substantial overlap at numerous levels. In this special issue, initiated by members of the EU-funded PRIME consortium ("Prevention and Remediation of Insulin Multimorbidity in Europe; www.prime-study.eu), the focus is on the comorbidities of metabolic disturbances, especially related to insulin signalling dysregulation and mental and neurological disorders. Thus, while obesity, type 2 diabetes, and metabolic syndrome are commonly known to be insulin-related disorders, the last decades have shown that neurodegenerative disorders, such as Alzheimer's disease, as well as neurodevelopment disorders, such as obsessive-compulsive disorder (OCD), autism spectrum disorders (ASDs) and attention deficit / hyperactivity disorder (ADHD) also fall into this category. The special issue draws together a series of basic and clinical review articles that describe the current knowledge and future perspectives regarding insulin comorbidities across a multidisciplinary group of experts.},
}

@article {pmid38678582,
year = {2024},
author = {Mayo, P and Pascual, J and Crisman, E and Domínguez, C and López, MG and León, R},
title = {Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.22045},
pmid = {38678582},
issn = {1098-1128},
support = {//Consejería de Sanidad, Comunidad de Madrid/ ; //Ministerio de Ciencia e Innovación/ ; //Instituto de Salud Carlos III/ ; //European Regional Development Fund/ ; //European Cooperation in Science and Technology/ ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget-directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.},
}

@article {pmid38678309,
year = {2024},
author = {Shanok, NA and Muzac, S and Derbin, B and Cabeza, E and Rodriguez, R},
title = {The effects of deep transcranial magnetic stimulation on Alzheimer's disease: a case report examining cognitive functioning, memory, and QEEG.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/13554794.2024.2346987},
pmid = {38678309},
issn = {1465-3656},
abstract = {Numerous treatment options are being studied for Alzheimer's disease (AD) given the rising prevalence of this condition worldwide. Transcranial Magnetic Stimulation (TMS) is a promising option for regulating specific neurological abnormalities pertaining to this condition. This case presents a patient with AD and co-occurring major depressive disorder that received 36 sessions of Deep TMS to the frontal and temporal lobes. This patient experienced improved general cognitive functioning and memory, remission from depression, and reduced slow-frequency theta activity in frontal and temporal sites. Following 7 months of weekly maintenance, additional improvements occurred. This report suggests that Deep TMS may be effective in mitigating AD symptoms, and maintenance sessions are advisable.},
}

@article {pmid38678292,
year = {2024},
author = {Oosthoek, M and Vermunt, L and de Wilde, A and Bongers, B and Antwi-Berko, D and Scheltens, P and van Bokhoven, P and Vijverberg, EGB and Teunissen, CE},
title = {Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer's disease: a systematic review.},
journal = {Alzheimer's research & therapy},
volume = {16},
number = {1},
pages = {93},
pmid = {38678292},
issn = {1758-9193},
mesh = {*Alzheimer Disease/cerebrospinal fluid/drug therapy/blood/diagnosis ; Humans ; *Biomarkers/cerebrospinal fluid/blood ; Clinical Trials as Topic/methods ; tau Proteins/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; },
abstract = {BACKGROUND: Clinical trials in Alzheimer's disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development.

METHODS: We systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01-01-2017 and 01-01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type.

RESULTS: We found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aβ (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers.

CONCLUSIONS: As the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets.},
}

*Alzheimer Disease/cerebrospinal fluid/drug therapy/blood/diagnosis
Humans
*Biomarkers/cerebrospinal fluid/blood
Clinical Trials as Topic/methods
tau Proteins/cerebrospinal fluid/blood
Amyloid beta-Peptides/cerebrospinal fluid/blood

@article {pmid38678262,
year = {2024},
author = {Xu, C and Mei, Y and Yang, R and Luo, Q and Zhang, J and Kou, X and Hu, J and Wang, Y and Li, Y and Chen, R and Zhang, Z and Yao, Y and Sima, J},
title = {Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer's disease by inhibiting neuroinflammation and neuronal necroptosis.},
journal = {Cell & bioscience},
volume = {14},
number = {1},
pages = {55},
pmid = {38678262},
issn = {2045-3701},
support = {82173804//National Natural Science Foundation of China/ ; 82001144//National Natural Science Foundation of China/ ; 3150120042//High-Level Talents Start-up Funding of China Pharmaceutical University/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.

RESULTS: We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD[+] depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.

CONCLUSIONS: Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.},
}

@article {pmid38677842,
year = {2024},
author = {Liu, FT and Zhai, SM and Gao, DF and Yang, SH and Zhao, BX and Lin, ZM},
title = {A highly sensitive ratiometric fluorescent probe for detecting HSO3[-]/SO3[2-] and viscosity change based on FRET/TICT mechanism.},
journal = {Analytica chimica acta},
volume = {1305},
number = {},
pages = {342588},
doi = {10.1016/j.aca.2024.342588},
pmid = {38677842},
issn = {1873-4324},
mesh = {*Fluorescent Dyes/chemistry/chemical synthesis ; *Fluorescence Resonance Energy Transfer ; Viscosity ; Humans ; Sulfur Dioxide/analysis ; Sulfites/analysis/chemistry ; Limit of Detection ; Quinolinium Compounds/chemistry ; },
abstract = {BACKGROUND: Sulfur dioxide (SO2) is a significant gas signaling molecule in organisms, and viscosity is a crucial parameter of the cellular microenvironment. They are both involved in regulating many physiological processes in the human body. However, abnormalities in SO2 and viscosity levels are associated with various diseases, such as cardiovascular disease, lung cancer, respiratory diseases, neurological disorders, diabetes and Alzheimer's disease. Hence, it is essential to explore novel and efficient fluorescent probes for simultaneously monitoring SO2 and viscosity in organisms.

RESULTS: We selected quinolinium salt with good stability, high fluorescence intensity, good solubility and low cytotoxicity as the fluorophore and developed a highly sensitive ratiometric probe QQD to identify SO2 and viscosity changes based on Förster resonance energy transfer/twisted intramolecular charge transfer (FRET/TICT) mechanism. Excitingly, compared with other probes for SO2 detection, QQD not only identified HSO3[-]/SO3[2-] with a large Stokes shift (218 nm), low detection limit (1.87 μM), good selectivity, high energy transfer efficiency (92 %) and wide recognition range (1.87-200 μM), but also identified viscosity with a 26-fold fluorescence enhancement and good linearity. Crucially, QQD was applied to detect HSO3[-]/SO3[2-] and viscosity in actual water and food samples. In addition, QQD had low toxicity and good photostability for imaging HSO3[-]/SO3[2-] and viscosity in cells. These results confirmed the feasibility and reliability of QQD for HSO3[-]/SO3[2-] and viscosity imaging and environmental detection.

SIGNIFICANCE: We reported a unique ratiometric probe QQD for detecting HSO3[-]/SO3[2-] and viscosity based on the quinolinium skeleton. In addition to detecting HSO3[-]/SO3[2-] and viscosity change in actual water and food samples, QQD could also monitor the variations of HSO3[-]/SO3[2-] and viscosity in cells, which provided an experimental basis for further exploration of the role of SO2 derivatives and viscosity in biological systems.},
}

*Fluorescent Dyes/chemistry/chemical synthesis
*Fluorescence Resonance Energy Transfer
Viscosity
Humans
Sulfur Dioxide/analysis
Sulfites/analysis/chemistry
Limit of Detection
Quinolinium Compounds/chemistry

@article {pmid38677813,
year = {2024},
author = {Jouatel, L and Charras, K},
title = {[Supporting psychobehavioral disorders at home and in institutions: a systemic approach].},
journal = {Soins. Gerontologie},
volume = {29},
number = {167},
pages = {8-13},
doi = {10.1016/j.sger.2024.02.003},
pmid = {38677813},
issn = {1268-6034},
mesh = {Humans ; Aged ; *Alzheimer Disease/psychology ; Home Care Services ; },
abstract = {Caring for people with Alzheimer's disease and related disorders is a complex process, that of a chronic illness. Psychological and behavioral symptoms associated to dementia can appear in all neuro-degenerative diseases to varying degrees, and depend on numerous factors that need to be understood in order to take appropriate action. We propose a systemic approach to psychological and behavioral symptoms, with a view to preventing their onset or reducing their severity.},
}

Humans
Aged
*Alzheimer Disease/psychology
Home Care Services

@article {pmid38677657,
year = {2024},
author = {Ko, VI and Ong, K and Cleveland, DW and Yu, H and Ravits, JM},
title = {CK1δ/ε kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation.},
journal = {Neurobiology of disease},
volume = {196},
number = {},
pages = {106516},
doi = {10.1016/j.nbd.2024.106516},
pmid = {38677657},
issn = {1095-953X},
abstract = {Hyperphosphorylated TAR DNA-binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons is the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and a group of neurodegenerative diseases collectively referred to as TDP-43 proteinopathies that includes frontotemporal dementia, Alzheimer's disease, and limbic onset age-related TDP-43 encephalopathy. The mechanism of TDP-43 phosphorylation is poorly understood. Previously we reported casein kinase 1 epsilon gene (CSNK1E gene encoding CK1ε protein) as being tightly correlated with phosphorylated TDP-43 (pTDP-43) pathology. Here we pursued studies to investigate in cellular models and in vitro how CK1ε and CK1δ (a closely related family sub-member) mediate TDP-43 phosphorylation in disease. We first validated the binding interaction between TDP-43 and either CK1δ and CK1ε using kinase activity assays and predictive bioinformatic database. We utilized novel inducible cellular models that generated translocated phosphorylated TDP-43 (pTDP-43) and cytoplasmic aggregation. Reducing CK1 kinase activity with siRNA or small molecule chemical inhibitors resulted in significant reduction of pTDP-43, in both soluble and insoluble protein fractions. We also established CK1δ and CK1ε are the primary kinases that phosphorylate TDP-43 compared to CK2α, CDC7, ERK1/2, p38α/MAPK14, and TTBK1, other identified kinases that have been implicated in TDP-43 phosphorylation. Throughout our studies, we were careful to examine both the soluble and insoluble TDP-43 protein fractions, the critical protein fractions related to protein aggregation diseases. These results identify CK1s as critical kinases involved in TDP-43 hyperphosphorylation and aggregation in cellular models and in vitro, and in turn are potential therapeutic targets by way of CK1δ/ε inhibitors.},
}

@article {pmid38677573,
year = {2024},
author = {Banerjee, S and Saha, D and Sharma, R and Jayadee, W and Puttarak, P and Chaiyakunapruk, N and Chaoroensup, R},
title = {Phytocannabinoids in neuromodulation: from omics to epigenetics.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {118201},
doi = {10.1016/j.jep.2024.118201},
pmid = {38677573},
issn = {1872-7573},
abstract = {BACKGROUND: Recent developments in metabolomics, transcriptomic and epigenetics open up new horizons regarding the pharmacological understanding of phytocannabinoids as neuromodulators in treating anxiety, depression, epilepsy, Alzheimer's, Parkinson's disease and autism.

METHODS: The present review is an extensive search in public databases, such as Google Scholar, Scopus, the Web of Science, and PubMed, to collect all the literature about the neurobiological roles of cannabis extract, cannabidiol, 9-tetrahydrocannabinol specially focused on metabolomics, transcriptomic, epigenetic, mechanism of action, in different cell lines, induced animal models and clinical trials. We used bioinformatics, network pharmacology and enrichment analysis to understand the effect of phytocannabinoids in neuromodulation.

RESULTS: Cannabidomics studies show wide variability of metabolites across different strains and varieties, which determine their medicinal and abusive usage, which is very important for its quality control and regulation. CB receptors interact with other compounds besides cannabidiol and Δ9-tetrahydrocannabinol, like cannabinol and Δ8-tetrahydrocannabinol. Phytocannabinoids interact with cannabinoid and non-cannabinoid receptors (GPCR, ion channels, and PPAR) to improve various neurodegenerative diseases. However, its abuse because of THC is also a problem found across different epigenetic and transcriptomic studies. Network enrichment analysis shows CNR1 expression in the brain and its interacting genes involve different pathways such as Rap1 signalling, dopaminergic synapse, and relaxin signalling. CBD protects against diseases like epilepsy, depression, and Parkinson's by modifying DNA and mitochondrial DNA in the hippocampus. Network pharmacology analysis of 8 phytocannabinoids revealed an interaction with 10 (out of 60) targets related to neurodegenerative diseases, with enrichment of ErbB and PI3K-Akt signalling pathways which helps in ameliorating neuro-inflammation in various neurodegenerative diseases. The effects of phytocannabinoids vary across sex, disease state, and age which suggests the importance of a personalized medicine approach for better success.

CONCLUSIONS: Phytocannabinoids present a range of promising neuromodulatory effects. It holds promise if utilized in a strategic way towards personalized neuropsychiatric treatment. However, just like any drug irrational usage may lead to unforeseen negative effects. Exploring neuro-epigenetics and systems pharmacology of major and minor phytocannabinoid combinations can lead to success.},
}

@article {pmid38677558,
year = {2024},
author = {Schwab, K and Lauer, D and Magbagbeolu, M and Theuring, F and Gasiorowska, A and Zadrozny, M and Harrington, CR and Wischik, CM and Niewiadomska, G and Riedel, G},
title = {Hydromethylthionine rescues synaptic SNARE proteins in a mouse model of tauopathies: interference by cholinesterase inhibitors.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {110955},
doi = {10.1016/j.brainresbull.2024.110955},
pmid = {38677558},
issn = {1873-2747},
abstract = {In clinical trials for Alzheimer's disease (AD), hydromethylthionine mesylate (HMTM) showed reduced efficacy when administered as an add-on to symptomatic treatments, while it produced a significant improvement of cognitive function when taken as monotherapy. Interference of cholinesterase inhibition with HMTM was observed also in a tau transgenic mouse model, where rivastigmine reduced the pharmacological activity of HMTM at multiple brain levels including hippocampal acetylcholine release, synaptosomal glutamate release and mitochondrial activity. Here, we examined the effect of HMTM, given alone or in combination with the acetylcholinesterase inhibitor, rivastigmine, at the level of expression of selected pre-synaptic proteins (syntaxin-1; SNAP-25, VAMP-2, synaptophysin-1, synapsin-1, α-synuclein) in brain tissue harvested from tau-transgenic Line 1 (L1) and wild-type mice using immunohistochemistry. L1 mice overexpress the tau-core unit that induces tau aggregation and results in an AD-like phenotype. Synaptic proteins were lower in hippocampus and cortex but greater in basal forebrain regions in L1 compared to wild-type mice. HMTM partially normalised the expression pattern of several of these proteins in basal forebrain. This effect was diminished when HMTM was administered in combination with rivastigmine, where mean protein expression seemed supressed. This was further confirmed by group-based correlation network analyses where important levels of co-expression correlations in basal forebrain regions were lost in L1 mice and partially re-established when HMTM was given alone but not in combination with rivastigmine. These data indicate a reduction in pharmacological activity of HMTM when given as an add-on therapy, a result that is consistent with the responses observed in the clinic. Attenuation of the therapeutic effects of HMTM by cholinergic treatments may have important implications for other potential AD therapies.},
}

@article {pmid38677530,
year = {2024},
author = {Ionel, CS and Mahjoub, M and Matar, TL},
title = {Aβ-protein polymerization in Alzheimer disease: Optimal control for nucleation parameter estimation.},
journal = {Journal of theoretical biology},
volume = {},
number = {},
pages = {111814},
doi = {10.1016/j.jtbi.2024.111814},
pmid = {38677530},
issn = {1095-8541},
abstract = {In this paper, we are interested in the modeling of Alzheimer's disease from the angle of the amyloid cascade hypothesis, where the pathogenic agent is the Aβ protein in its oligomeric form. The formation dynamics of this pathogenic form is modeled by a Becker-Doring type model where APP (Amyloid Precursor Protein) protein, after cleavage by specific enzymes, forms monomeric Aβ proteins, which, by polymerization and/or nucleation, lead to the formation of oligomeric Aβ. We propose an optimal control problem to estimate the rate of nucleation which seems to be at the base of this amyloid cascade hypothesis and for which no (experimental) measurement exists for the moment.},
}

@article {pmid38677445,
year = {2024},
author = {Hölscher, C},
title = {Glucagon-like peptide-1 class drugs show clear protective effects in Parkinson's and Alzheimer's disease clinical trials: A revolution in the making?.},
journal = {Neuropharmacology},
volume = {253},
number = {},
pages = {109952},
doi = {10.1016/j.neuropharm.2024.109952},
pmid = {38677445},
issn = {1873-7064},
abstract = {Parkinson's disease (PD) is a complex syndrome for which there is no disease-modifying treatment on the market. However, a group of drugs from the Glucagon-like peptide-1 (GLP-1) class have shown impressive improvements in clinical phase II trials. Exendin-4 (Bydureon), Liraglutide (Victoza, Saxenda) and Lixisenatide (Adlyxin), drugs that are on the market as treatments for diabetes, have shown clear effects in improving motor activity in patients with PD in phase II clinical trials. In addition, Liraglutide has shown improvement in cognition and brain shrinkage in a phase II trial in patients with Alzheimer disease (AD). Two phase III trials testing the GLP-1 drug semaglutide (Wegovy, Ozempic, Rybelsus) are ongoing. This perspective article will summarize the clinical results obtained so far in this novel research area. We are at a crossroads where GLP-1 class drugs are emerging as a new treatment strategy for PD and for AD. Newer drugs that have been designed to enter the brain easier are being developed already show improved effects in preclinical studies compared with the older GLP-1 class drugs that had been developed to treat diabetes. The future looks bright for new treatments for AD and PD.},
}

@article {pmid38677034,
year = {2024},
author = {He, H and Xie, J and Huang, D and Zhang, M and Zhao, X and Ying, Y and Wang, J},
title = {DRTerHGAT: A drug repurposing method based on the ternary heterogeneous graph attention network.},
journal = {Journal of molecular graphics & modelling},
volume = {130},
number = {},
pages = {108783},
doi = {10.1016/j.jmgm.2024.108783},
pmid = {38677034},
issn = {1873-4243},
abstract = {Drug repurposing is an effective method to reduce the time and cost of drug development. Computational drug repurposing can quickly screen out the most likely associations from large biological databases to achieve effective drug repurposing. However, building a comprehensive model that integrates drugs, proteins, and diseases for drug repurposing remains challenging. This study proposes a drug repurposing method based on the ternary heterogeneous graph attention network (DRTerHGAT). DRTerHGAT designs a novel protein feature extraction process consisting of a large-scale protein language model and a multi-task autoencoder, so that protein features can be extracted accurately and efficiently from amino acid sequences. The ternary heterogeneous graph of drug-protein-disease comprehensively considering the relationships among the three types of nodes, including three homogeneous and three heterogeneous relationships. Based on the graph and the extracted protein features, the deep features of the drugs and the diseases are extracted by graph convolutional networks (GCN) and heterogeneous graph node attention networks (HGNA). In the experiments, DRTerHGAT is proven superior to existing advanced methods and DRTerHGAT variants. DRTerHGAT's powerful ability for drug repurposing is also demonstrated in Alzheimer's disease.},
}

@article {pmid38676929,
year = {2024},
author = {Pandey, RS and Arnold, M and Batra, R and Krumsiek, J and Kotredes, KP and Garceau, D and Williams, H and Sasner, M and Howell, GR and Kaddurah-Daouk, R and Carter, GW},
title = {Metabolomics profiling reveals distinct, sex-specific signatures in serum and brain metabolomes in mouse models of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13851},
pmid = {38676929},
issn = {1552-5279},
support = {U54 AG054345/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation.

METHODS: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age.

RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum.

DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD.

HIGHLIGHTS: This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex-specific metabolic differences, similar to human study cohorts. The early-onset 5XFAD mouse model primarily alters brain metabolites while the late-onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum.},
}

@article {pmid38676749,
year = {2024},
author = {Bao, YW and Wang, ZJ and Guo, LL and Bai, GJ and Feng, Y and Zhao, GD},
title = {Expression of regional brain amyloid-β deposition with [[18F]]Flutemetamol in Centiloid scale -a multi-site study.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {38676749},
issn = {1432-1920},
abstract = {PURPOSE: The Centiloid project helps calibrate the quantitative amyloid-β (Aβ) load into a unified Centiloid (CL) scale that allows data comparison across multi-site. How the smaller regional amyloid converted into CL has not been attempted. We first aimed to express regional Aβ deposition in CL using [[18F]]Flutemetamol and evaluate regional Aβ deposition in CL with that in standardized uptake value ratio (SUVr). Second, we aimed to determine the presence or absence of focal Aβ deposition by measuring regional CL in equivocal cases showing negative global CL.

METHODS: Following the Centiloid project pipeline, Level-1 replication, Level-2 calibration, and quality control were completed to generate corresponding Centiloid conversion equations to convert SUVr into Centiloid at regional levels. In equivocal cases, the regional CL was compared with visual inspection to evaluate regional Aβ positivity.

RESULTS: 14 out of 16 regional conversions from [[18F]]Flutemetamol SUVr to Centiloid successfully passed the quality control, showing good reliability and relative variance, especially precuneus/posterior cingulate and prefrontal regions with good stability for Centiloid scaling. The absence of focal Aβ deposition could be detected by measuring regional CL, showing a high agreement rate with visual inspection. The regional Aβ positivity in the bilateral anterior cingulate cortex was most prevalent in equivocal cases.

CONCLUSION: The expression of regional brain Aβ deposition in CL with [[18F]]Flutemetamol has been attempted in this study. Equivocal cases had focal Aβ deposition that can be detected by measuring regional CL.},
}

@article {pmid38676673,
year = {2024},
author = {Berezutsky, MA and Durnova, NA and Andronova, TA},
title = {[Ginkgolide B: mechanisms of neurobiological effects, prospects for use in the therapy of Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {124},
number = {4},
pages = {22-27},
doi = {10.17116/jnevro202412404122},
pmid = {38676673},
issn = {1997-7298},
mesh = {*Ginkgolides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Lactones/therapeutic use/pharmacology ; *Brain-Derived Neurotrophic Factor/metabolism ; *Ginkgo biloba ; Animals ; Neurons/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism ; Microglia/drug effects/metabolism ; Memory/drug effects ; },
abstract = {The review presents an analysis of experimental data on the study of neurobiological effects of ginkgolide B, which may find application in the therapy of Alzheimer's disease (AD). Ginkgolide B is a diterpene trilactone isolated from the leaves of the relict woody plant Ginkgo biloba L., which has been used for thousands of years in traditional Chinese medicine as a neuroprotective agent. In recent years, this compound has attracted attention because of its wide range of neurobiological effects. The neuroprotective effect of ginkgolide B on brain neurons when exposed to various neurotoxins has been established. This compound has also been shown to effectively protect neurons from the effects of beta-amyloid. Studies have revealed the ability of ginkgolide B to reduce microglia activity and regulate neurotransmitter release. In vivo experiments have shown that this substance significantly increases the expression of brain-derived neurotrophic factor (BDNF) and improves cognitive functions, including memory and learning. It is concluded that ginkgolide B, apparently, may find application in the future as a multi-targeted agent of complex therapy of AD.},
}

*Ginkgolides/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy
Humans
*Neuroprotective Agents/therapeutic use/pharmacology
*Lactones/therapeutic use/pharmacology
*Brain-Derived Neurotrophic Factor/metabolism
*Ginkgo biloba
Animals
Neurons/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Brain/drug effects/metabolism
Microglia/drug effects/metabolism
Memory/drug effects

@article {pmid38676671,
year = {2024},
author = {Kashchenko, SA and Eranova, AA and Chuguy, EV},
title = {[Glymphatic dysfunction and sleep disorders: indirect effects on Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {124},
number = {4},
pages = {7-12},
doi = {10.17116/jnevro20241240417},
pmid = {38676671},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/physiopathology/metabolism ; *Glymphatic System/physiopathology/metabolism ; *Sleep Wake Disorders/physiopathology/metabolism ; *Amyloid beta-Peptides/metabolism ; Sleep Deprivation/physiopathology/complications/metabolism ; },
abstract = {Modern research raises the question of the potentially significant role of glymphatic dysfunction in the development of neurodegeneration and pathological aging. The exact molecular mechanisms are not yet fully understood, but there is ample evidence of a link between sleep deprivation and decreased clearance of β-amyloid and other neurotoxin proteins that are associated with the development of neurodegenerative diseases, particularly Alzheimer's disease. The review analyzes current scientific information in this area of research, describes the latest scientific discoveries of the features of the glymphatic system, and also illustrates studies of markers that presumably indicate a deterioration in the glymphatic system. The relationship between sleep deprivation and pathophysiological mechanisms associated with neurodegenerative diseases is considered, and potential targets that can be used to treat or delay the development of these disorders are noted.},
}

Humans
*Alzheimer Disease/physiopathology/metabolism
*Glymphatic System/physiopathology/metabolism
*Sleep Wake Disorders/physiopathology/metabolism
*Amyloid beta-Peptides/metabolism
Sleep Deprivation/physiopathology/complications/metabolism

@article {pmid38676652,
year = {2024},
author = {Sahayaraj, AE and Abdul Vahid, A and Dhara, A and Babu, AT and Vijayan, V},
title = {Role of G326 in Determining the Aggregation Propensity of R3 Tau Repeat: Insights from Studies on R1R3 Tau Construct.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.4c00123},
pmid = {38676652},
issn = {1520-5207},
abstract = {The Microtubule-binding repeat region (MTBR) of Tau has been studied extensively due to its pathological implications in neurodegenerative diseases like Alzheimer's disease. The pathological property of MTBR is mainly due to the R3 repeat's high propensity for self-aggregation, highlighting the critical molecular grammar of the repeat. Utilizing the R1R3 construct (WT) and its G326E mutant (EE), we determine the distinct characteristics of various peptide segments that modulate the aggregation propensity of the R3 repeat using NMR spectroscopy. Through time-dependent experiments, we have identified [317]KVTSKCGS[324] in R3 repeat as the aggregation initiating motif (AIM) due to its role at the initial stages of aggregation. The G326E mutation induces changes in conformation and dynamics at the AIM, thereby effectively abrogating the aggregation propensity of the R1R3 construct. We further corroborate our findings through MD simulations and propose that AIM is a robust site of interest for tauopathy drug design.},
}

@article {pmid38676563,
year = {2024},
author = {Schneider, C and Prokopiou, PC and Papp, KV and Engels-Domínguez, N and Hsieh, S and Juneau, TA and Schultz, AP and Rentz, DM and Sperling, RA and Johnson, KA and Jacobs, HIL},
title = {Atrophy links lower novelty-related locus coeruleus connectivity to cognitive decline in preclinical AD.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13839},
pmid = {38676563},
issn = {1552-5279},
support = {P41EB022544/NH/NIH HHS/United States ; P41EEB015896/NH/NIH HHS/United States ; S10OD018035/NH/NIH HHS/United States ; S10RR021110/NH/NIH HHS/United States ; S10OD010364/NH/NIH HHS/United States ; S10RR023401/NH/NIH HHS/United States ; S10RR023043/NH/NIH HHS/United States ; 1S10RR019307/NH/NIH HHS/United States ; P01AG036694/NH/NIH HHS/United States ; R01AG046396/NH/NIH HHS/United States ; T32EB013180/NH/NIH HHS/United States ; R01AG062559/NH/NIH HHS/United States ; R01AG068062/NH/NIH HHS/United States ; R01AG082006/NH/NIH HHS/United States ; R21AG074220/NH/NIH HHS/United States ; 1R21AG081681-01/NH/NIH HHS/United States ; AARG-22-920434/ALZ/Alzheimer's Association/United States ; },
abstract = {INTRODUCTION: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FCLC-MTL) on cortical atrophy across Braak stage regions and its impact on cognition.

METHODS: We analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FCLC-MTL with longitudinal atrophy and cognition with and without Aβ moderation.

RESULTS: Cross-sectionally, lower FCLC-MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FCLC-MTL at elevated levels of Aβ, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FCLC-MTL and subsequent cognitive decline.

DISCUSSION: FCLC-MTL is implicated in Aβ-related cortical atrophy, suggesting that LC-MTL connectivity could confer neuroprotective effects in preclinical AD.

HIGHLIGHTS: Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aβ-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aβ burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.},
}

@article {pmid38676511,
year = {2024},
author = {Li, H and Hua, Q and Cheng, S and Liu, X and Cai, Q and Zhang, J and Peng, T and Li, J and Wang, C and Liang, C and Shi, Y and Wang, X and Tan, Y},
title = {The NeuroProtect Formula: A Preventive Approach to AD Targeting the HIF-1/PI3K-AKT Signaling Pathway Evaluated through In Vivo, In Vitro, and Network Pharmacology Approaches.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073311518240416070410},
pmid = {38676511},
issn = {1875-5402},
abstract = {OBJECTIVE: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with limited options for reversing its middle-to-late stages. Early intervention is crucial to slow down disease progression. This study aimed to investigate the potential of the NeuroProtect (NP) formula, a combination of geniposide and Panax notoginseng saponins, in preventing AD. We evaluated the effects of the NP formula on amyloid plaque accumulation, neuronal degeneration, and molecular signaling pathways using in vivo and in vitro models.

METHODS: To predict functional pathways and potential downstream targets of NP intervention, we employed network pharmacology. The preventative impact of the NP formula was assessed using APP/PS1 mice. We conducted HE staining, ELISA assay, Golgi staining, and immunohistochemistry to detect the protective effect of NP. Additionally, cell experiments were performed to assess cell activity and target protein expression.

RESULTS: Network pharmacology analysis revealed 145 drug-disease interactions and identified 5 core active targets associated with AD. Molecular docking results demonstrated strong binding affinity between the components of the NP formula (GP, GN-Rb1, GN-Rg1, NS-R1) and target proteins (STAT3, HIF1A, TLR4, mTOR, VEGFA). Notably, the binding energy between NS-R1 and mTOR was -11.4kcal/mol. Among the top 10 enriched KEGG pathways, the HIF-1 and PI3K-AKT signaling pathways were highlighted. In vivo experiments demonstrated that the NP formula significantly ameliorated pathological changes, decreased the Aβ42/Aβ40 ratio in the hippocampus and cortex, and increased dendritic spine density in the CA1 region during the early stage of AD. In vitro experiments further illustrated the NP formula's ability to reverse the inhibitory effects of Aβ25-35 on cell viability and regulate the expression of Tlr4, Mtor, Hif1a, Stat3, and Vegfa.

CONCLUSION: Our findings suggest that NP exhibits neuroprotective effects during the early stages of AD, positioning it as a potential candidate for AD prevention. The NP formula may exert its preventive effects through the HIF-1/PI3K-AKT signaling pathway, with mTOR identified as a key target.},
}

@article {pmid38676493,
year = {2024},
author = {Selvaraj, S and Weerasinghe, L},
title = {The Role of Nanotechnology in Understanding the Pathophysiology of Traumatic Brain Injury.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249291999240418112531},
pmid = {38676493},
issn = {1875-6166},
abstract = {Recently, traumatic brain injury (TBI) has been a growing disorder due to frequent brain dysfunction. The Glasgow Coma Scale expresses TBI as classified as having mild, moderate, or severe brain effects, according to the effects on the brain. Brain receptors undergo various modifications in their pathology through chemical synaptic pathways, leading to depression, Alzheimer's, and Parkinson's disease. These brain disorders can be controlled using central receptors such as dopamine, glutamate, and γ-aminobutyric acid, which are clearly explained in this review. Furthermore, there are many complications in TBI's clinical trials and diagnostics, leading to insignificant treatment, causing permanent neuro-damage, physical disability, and even death. Bio-screening and conventional molecular-based therapies are inappropriate due to poor preclinical testing and delayed recovery. Hence, modern nanotechnology utilizing nanopulsed laser therapy and advanced nanoparticle insertion will be suitable for TBI's diagnostics and treatment. In recent days, nanotechnology has an important role in TBI control and provides a higher success rate than conventional therapies. This review highlights the pathophysiology of TBI by comprising the drawbacks of conventional techniques and supports suitable modern alternates for treating TBI.},
}

@article {pmid38676489,
year = {2024},
author = {Vishwas, S and Bashir, B and Birla, D and Khandale, N and Chaitanya, MVNL and Chellappan, DK and Gupta, G and Negi, P and Dua, K and Singh, SK},
title = {Neuroprotective Role of Phytoconstituents-based Nanoemulsion for the Treatment of Alzheimer's Disease.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266296001240327090111},
pmid = {38676489},
issn = {1873-4294},
abstract = {Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorder (ND), affecting more than 44 million individuals globally as of 2023. It is characterized by cognitive dysfunction and an inability to perform daily activities. The progression of AD is associated with the accumulation of amyloid beta (Aβ), the formation of neurofibrillary tangles (NFT), increased oxidative stress, neuroinflammation, mitochondrial dysfunction, and endoplasmic reticulum stress. Presently, various phytomedicines and their bioactive compounds have been identified for their neuroprotective effects in reducing oxidative stress, alleviating neuroinflammation, and mitigating the accumulation of Aβ and acetylcholinesterase enzymes in the hippocampus and cerebral cortex regions of the brain. However, despite demonstrating promising anti-Alzheimer's effects, the clinical utilization of phytoconstituents remains limited in scope. The key factor contributing to this limitation is the challenges inherent in traditional drug delivery systems, which impede their effectiveness and efficiency. These difficulties encompass insufficient drug targeting, restricted drug solubility and stability, brief duration of action, and a lack of control over drug release. Consequently, these constraints result in diminished bioavailability and insufficient permeability across the blood-brain barrier (BBB). In response to these challenges, novel drug delivery systems (NDDS) founded on nanoformulations have emerged as a hopeful strategy to augment the bioavailability and BBB permeability of bioactive compounds with poor solubility. Among these systems, nanoemulsion (NE) have been extensively investigated for their potential in targeting AD. NE offers several advantages, such as ease of preparation, high drug loading, and high stability. Due to their nanosize droplets, NE also improves gut and BBB permeability leading to enhanced permeability of the drug in systemic circulation and the brain. Various studies have reported the testing of NE-based phytoconstituents and their bioactives in different animal species, including transgenic, Wistar, and Sprague-Dawley (SD) rats, as well as mice. However, transgenic mice are commonly employed in AD research to analyze the effects of Aβ. In this review, various aspects such as the neuroprotective role of various phytoconstituents, the challenges associated with conventional drug delivery, and the need for NDDS, particularly NE, are discussed. Various studies involving phytoconstituent-based NE for the treatment of AD are also discussed.},
}

@article {pmid38676452,
year = {2024},
author = {Mather, M},
title = {The emotion paradox in the aging body and brain.},
journal = {Annals of the New York Academy of Sciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/nyas.15138},
pmid = {38676452},
issn = {1749-6632},
support = {R01AG025340/AG/NIA NIH HHS/United States ; R01AG080652/AG/NIA NIH HHS/United States ; R01AG082073/AG/NIA NIH HHS/United States ; },
abstract = {With age, parasympathetic activity decreases, while sympathetic activity increases. Thus, the typical older adult has low heart rate variability (HRV) and high noradrenaline levels. Younger adults with this physiological profile tend to be unhappy and stressed. Yet, with age, emotional experience tends to improve. Why does older adults' emotional well-being not suffer as their HRV decreases? To address this apparent paradox, I present the autonomic compensation model. In this model, failing organs, the initial phases of Alzheimer's pathology, and other age-related diseases trigger noradrenergic hyperactivity. To compensate, older brains increase autonomic regulatory activity in the pregenual prefrontal cortex (PFC). Age-related declines in nerve conduction reduce the ability of the pregenual PFC to reduce hyperactive noradrenergic activity and increase peripheral HRV. But these pregenual PFC autonomic compensation efforts have a significant impact in the brain, where they bias processing in favor of stimuli that tend to increase parasympathetic activity (e.g., stimuli that increase feelings of safety) and against stimuli that tend to increase sympathetic activity (e.g., threatening stimuli). In summary, the autonomic compensation model posits that age-related chronic sympathetic/noradrenergic hyperactivity stimulates regulatory attempts that have the side effect of enhancing emotional well-being.},
}

@article {pmid38676443,
year = {2024},
author = {Hu, HY and Hu, H and Jiang, J and Bi, YL and Sun, Y and Ou, YN and Tan, L and Yu, JT},
title = {Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13837},
pmid = {38676443},
issn = {1552-5279},
support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 82071201//National Natural Science Foundation of China/ ; 82271475//National Natural Science Foundation of China/ ; 2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; 2022QD002//Research Start-up Fund of Huashan Hospital/ ; 3030277001//Excellence 2025 Talent Cultivation Program at Fudan University/ ; //ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute/ ; //State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University/ ; },
abstract = {INTRODUCTION: This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition.

METHODS: Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age = 65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions.

RESULTS: LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)-tau and total (t)-tau levels, and poorer cognition. Tau pathologies mediated the heart-cognition relationships. Cardiac parameters were higher in stage 2 and suspected non-Alzheimer's pathology groups than controls.

DISCUSSION: These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition.

HIGHLIGHTS: Various subclinical alterations in the left heart related to poorer cognition. Subclinical cardiac changes related to tau pathologies in cognitively normal adults. Tau pathologies mediated the heart-cognition relationships. Subclinical cardiac changes related to the AD continuum, especially to stage 2. The accumulation of cardiac alterations magnified their damage to the brain.},
}

@article {pmid38676301,
year = {2024},
author = {Cayir, S and Volpi, T and Toyonaga, T and Gallezot, JD and Yang, Y and Sadabad, FE and Mulnix, T and Mecca, AP and Fesharaki-Zadeh, A and Matuskey, D},
title = {Relationship between neuroimaging and cognition in frontotemporal dementia: An FDG-PET and structural MRI study.},
journal = {Journal of neuroimaging : official journal of the American Society of Neuroimaging},
volume = {},
number = {},
pages = {},
doi = {10.1111/jon.13206},
pmid = {38676301},
issn = {1552-6569},
support = {P30AG066508/GF/NIH HHS/United States ; },
abstract = {BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative condition with a prevalence comparable to Alzheimer's disease for patients under 65 years of age. Limited studies have examined the association between cognition and neuroimaging in FTD using different imaging modalities.

METHODS: We examined the association of cognition using Montreal Cognitive Assessment (MoCA) with both gray matter (GM) volume and glucose metabolism using magnetic resonance imaging and fluorodeoxyglucose (FDG)-PET in 21 patients diagnosed with FTD. Standardized uptake value ratio (SUVR) using the brainstem as a reference region was the primary outcome measure for FDG-PET. Partial volume correction was applied to PET data to account for disease-related atrophy.

RESULTS: Significant positive associations were found between whole-cortex GM volume and MoCA scores (r = 0.46, p = .04). The association between whole-cortex FDG SUVR and MoCA scores was not significant (r = 0.37, p = .09). GM volumes of the frontal cortex (r = 0.54, p = .01), caudate (r = 0.62, p<.01), and insula (r = 0.57, p<.01) were also significantly correlated with MoCA, as were SUVR values of the insula (r = 0.51, p = .02), thalamus (r = 0.48, p = .03), and posterior cingulate cortex (PCC) (r = 0.47, p = .03).

CONCLUSIONS: Whole-cortex atrophy is associated with cognitive dysfunction, and this association is larger than for whole-cortex hypometabolism as measured with FDG-PET. At the regional level, focal atrophy and/or hypometabolism in the frontal cortex, insula, PCC, thalamus, and caudate seem to be important for the decline of cognitive function in FTD. Furthermore, these results highlight how functional and structural changes may not overlap and might contribute to cognitive dysfunction in FTD in different ways.},
}

@article {pmid38675648,
year = {2024},
author = {Li, Q and Wei, P and Li, Y and Fu, Y},
title = {Optimization of Extraction Process and Analysis of Biological Activity of Flavonoids from Leaves of Cultivated 'Qi-Nan' Agarwood.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {8},
pages = {},
pmid = {38675648},
issn = {1420-3049},
support = {（32171702）//National Natural Science Foundation of China/ ; },
mesh = {*Flavonoids/analysis/chemistry/isolation & purification ; *Plant Leaves/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Antioxidants/chemistry/pharmacology ; Chromatography, High Pressure Liquid ; Thymelaeaceae/chemistry ; },
abstract = {Currently, the planting of 'Qi-Nan' is continuously increasing, yet a substantial amount of 'Qi-Nan' leaves have not been properly exploited. To improve the 'Qi-Nan' tree 's utilization value, 'Qi-Nan' leaves were used as a raw material. An ultrasound-assisted method was performed to obtain the flavonoids from the 'Qi-Nan' leaves, followed by optimization of the extraction factors using a one-way and response surface methodology to enhance the extraction of flavonoids. Subsequently, the composition of the flavonoids, as well as their bioactive abilities, were analyzed by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and in vitro activity testing methods. The findings demonstrated that a 1:50 material-to-liquid ratio, 60% ethanol concentration, and ultrasound-assisted extraction time of 30 min were the ideal procedures for extracting flavonoids (flavonoid content: 6.68%). Meanwhile, the 'Qi-Nan' leaves possessed the antioxidant and medicinal potential to prevent diabetes and Alzheimer 's disease, as evidenced by the semi-inhibitory concentrations (IC50 values) of flavonoid extracts for scavenging DPPH[•] free radicals, scavenging ABTS[•+] free radicals, inhibiting acetylcholinesterase, and inhibiting α-glucosidase, which were 12.64 μg/mL, 66.58 μg/mL, 102.31 μg/mL, and 38.76 μg/mL, respectively, which indicated that the 'Qi-Nan' leaves possessed the properties of antioxidant and medicinal potential for the prevention of Alzheimer 's disease and diabetes.},
}

*Flavonoids/analysis/chemistry/isolation & purification
*Plant Leaves/chemistry
*Plant Extracts/chemistry/pharmacology
*Antioxidants/chemistry/pharmacology
Chromatography, High Pressure Liquid
Thymelaeaceae/chemistry

@article {pmid38675602,
year = {2024},
author = {Wu, X and Ze, X and Qin, S and Zhang, B and Li, X and Gong, Q and Zhang, H and Zhu, Z and Xu, J},
title = {Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {8},
pages = {},
pmid = {38675602},
issn = {1420-3049},
support = {No. 81874289, 82373743//National Natural Science Foundation of China/ ; CPU2018GY04//China Pharmaceutical University/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; *Molecular Docking Simulation ; *Drug Design ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; Cell Line, Tumor ; Sulfur/chemistry ; Structure-Activity Relationship ; Acridines/chemistry/pharmacology/chemical synthesis ; Tacrine/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 μM) with pyrimidone compound 5 (GSK-3β: IC50 = 3 μM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3β (GSK-3β). The optimal compound 18a possessed potent dual AChE/GSK-3β inhibition (AChE: IC50 = 0.047 ± 0.002 μM, GSK-3β: IC50 = 0.930 ± 0.080 μM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 μM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
*Acetylcholinesterase/metabolism/chemistry
*Molecular Docking Simulation
*Drug Design
*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism
Cell Line, Tumor
Sulfur/chemistry
Structure-Activity Relationship
Acridines/chemistry/pharmacology/chemical synthesis
Tacrine/chemistry/pharmacology/chemical synthesis
Molecular Structure

@article {pmid38675584,
year = {2024},
author = {Porfetye, AT and Stege, P and Rebollido-Rios, R and Hoffmann, D and Schrader, T and Vetter, IR},
title = {How Do Molecular Tweezers Bind to Proteins? Lessons from X-ray Crystallography.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {8},
pages = {},
pmid = {38675584},
issn = {1420-3049},
support = {SFB 1093, project A3 and Z2//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Crystallography, X-Ray ; *Protein Binding ; Ligands ; Humans ; Models, Molecular ; 14-3-3 Proteins/chemistry/metabolism ; Binding Sites ; Proteins/chemistry ; Protein Conformation ; },
abstract = {To understand the biological relevance and mode of action of artificial protein ligands, crystal structures with their protein targets are essential. Here, we describe and investigate all known crystal structures that contain a so-called "molecular tweezer" or one of its derivatives with an attached natural ligand on the respective target protein. The aromatic ring system of these compounds is able to include lysine and arginine side chains, supported by one or two phosphate groups that are attached to the half-moon-shaped molecule. Due to their marked preference for basic amino acids and the fully reversible binding mode, molecular tweezers are able to counteract pathologic protein aggregation and are currently being developed as disease-modifying therapies against neurodegenerative diseases such as Alzheimer's and Parkinson's disease. We analyzed the corresponding crystal structures with 14-3-3 proteins in complex with mono- and diphosphate tweezers. Furthermore, we solved crystal structures of two different tweezer variants in complex with the enzyme Δ[1]-Pyrroline-5-carboxyl-dehydrogenase (P5CDH) and found that the tweezers are bound to a lysine and methionine side chain, respectively. The different binding modes and their implications for affinity and specificity are discussed, as well as the general problems in crystallizing protein complexes with artificial ligands.},
}

Crystallography, X-Ray
*Protein Binding
Ligands
Humans
Models, Molecular
14-3-3 Proteins/chemistry/metabolism
Binding Sites
Proteins/chemistry
Protein Conformation

@article {pmid38675490,
year = {2024},
author = {Stanciu, GD and Ababei, DC and Solcan, C and Uritu, CM and Craciun, VC and Pricope, CV and Szilagyi, A and Tamba, BI},
title = {Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer's Disease Treatment.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {4},
pages = {},
pmid = {38675490},
issn = {1424-8247},
support = {PN-III-P1-1.1-PD-2021-0466, within PNCDI III//This work was supported by a grant from the Ministry of Research, Innovation and Digitaliza-tion, CNCS-UEFISCDI/ ; },
abstract = {Despite decades of rigorous research and numerous clinical trials, Alzheimer's disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive. Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing. Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir[®] Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aβ plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment. Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment.},
}

@article {pmid38675451,
year = {2024},
author = {Patil, SP and Kuehn, BR},
title = {Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer's Disease Cell Model.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {4},
pages = {},
pmid = {38675451},
issn = {1424-8247},
support = {NIRP-12-258855/ALZ/Alzheimer's Association/United States ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.},
}

@article {pmid38675428,
year = {2024},
author = {Calenda, S and Catarzi, D and Varano, F and Vigiani, E and Volpini, R and Lambertucci, C and Spinaci, A and Trevisan, L and Grieco, I and Federico, S and Spalluto, G and Novello, G and Salmaso, V and Moro, S and Colotta, V},
title = {Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {4},
pages = {},
pmid = {38675428},
issn = {1424-8247},
support = {RICATEN2021-2023Colotta//University of Florence/ ; 2017MT3993_004//Italian Ministry of University and Research-PRIN2017/ ; },
abstract = {Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized (1-32), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold (13-32), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency (23, IC50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor-kinase interactions.},
}

@article {pmid38675373,
year = {2024},
author = {Tariq, S and Rahim, F and Ullah, H and Sarfraz, M and Hussain, R and Khan, S and Khan, MU and Rehman, W and Hussain, A and Bhat, MA and Farooqi, MK and Shah, SAA and Iqbal, N},
title = {Synthesis, In Vitro Biological Evaluation and Molecular Modeling of Benzimidazole-Based Pyrrole/Piperidine Hybrids Derivatives as Potential Anti-Alzheimer Agents.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {4},
pages = {},
pmid = {38675373},
issn = {1424-8247},
abstract = {Benzimidazole-based pyrrole/piperidine analogs (1-26) were synthesized and then screened for their acetylcholinesterase and butyrylcholinesterase activities. All the analogs showed good to moderate cholinesterase activities. Synthesized compounds (1-13) were screened in cholinesterase enzyme inhibition assays and showed AChE activities in the range of IC50 = 19.44 ± 0.60 µM to 36.05 ± 0.4 µM against allanzanthane (IC50 = 16.11 ± 0.33 µM) and galantamine (IC50 = 19.34 ± 0.62 µM) and varied BuChE inhibitory activities, with IC50 values in the range of 21.57 ± 0.61 µM to 39.55 ± 0.03 µM as compared with standard allanzanthane (IC50 = 18.14 ± 0.05 µM) and galantamine (IC50 = 21.45 ± 0.21 µM). Similarly, synthesized compounds (14-26) were also subjected to tests to determine their in vitro AChE inhibitory activities, and the results obtained corroborated that all the compounds showed varied activities in the range of IC50 = 22.07 ± 0.13 to 42.01 ± 0.02 µM as compared to allanzanthane (IC50 = 20.01 ± 0.12 µM) and galantamine (IC50 = 18.05 ± 0.31 µM) and varied BuChE inhibitory activities, with IC50 values in the range of 26.32 ± 0.13 to 47.03 ± 0.15 µM as compared to standard allanzanthane (IC50 = 18.14 ± 0.05 µM) and galantamine (IC50 = 21.45 ± 0.21 µM). Binding interactions of the most potent analogs were confirmed through molecular docking studies. The active analogs 2, 4, 10 and 13 established numerous interactions with the active sites of targeted enzymes, with docking scores of -10.50, -9.3, -7.73 and -7.8 for AChE and -8.97, -8.2, -8.20 and -7.6 for BuChE, respectively.},
}

@article {pmid38675371,
year = {2024},
author = {Chow, TW and Raupp, M and Reynolds, MW and Li, S and Kaeser, GE and Chun, J},
title = {Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer's Disease Risk: A Retrospective Cohort Proof-of-Concept Study.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {4},
pages = {},
pmid = {38675371},
issn = {1424-8247},
support = {R01AG071465/AG/NIA NIH HHS/United States ; R01AG065541/AG/NIA NIH HHS/United States ; R56AG073965/AG/NIA NIH HHS/United States ; },
abstract = {Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer's disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted.},
}

@article {pmid38675104,
year = {2024},
author = {Giorgi, C and Lombardozzi, G and Ammannito, F and Scenna, MS and Maceroni, E and Quintiliani, M and d'Angelo, M and Cimini, A and Castelli, V},
title = {Brain Organoids: A Game-Changer for Drug Testing.},
journal = {Pharmaceutics},
volume = {16},
number = {4},
pages = {},
pmid = {38675104},
issn = {1999-4923},
support = {PON R&I 2014-2020 FSE-REACT EU-CUP D.M. 1062/2021 E15F21004290001//European Union/ ; NextGenerationEU under the Italian University and Research (MUR) National Innovation Eco-system grant ECS00000041 -VITALITY -CUP E13C22001060006//European Union/ ; mD.M. 31 December 2021 and D.D. March 18, 2022-Project n. F/310074/02/X56 -CUP: B19J23000180005//Ministry of Enterprises and Made in Italy/ ; },
abstract = {Neurological disorders are the second cause of death and the leading cause of disability worldwide. Unfortunately, no cure exists for these disorders, but the actual therapies are only able to ameliorate people's quality of life. Thus, there is an urgent need to test potential therapeutic approaches. Brain organoids are a possible valuable tool in the study of the brain, due to their ability to reproduce different brain regions and maturation stages; they can be used also as a tool for disease modelling and target identification of neurological disorders. Recently, brain organoids have been used in drug-screening processes, even if there are several limitations to overcome. This review focuses on the description of brain organoid development and drug-screening processes, discussing the advantages, challenges, and limitations of the use of organoids in modeling neurological diseases. We also highlighted the potential of testing novel therapeutic approaches. Finally, we examine the challenges and future directions to improve the drug-screening process.},
}

@article {pmid38674921,
year = {2024},
author = {Wang, W and Pan, D and Liu, Q and Chen, X and Wang, S},
title = {L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review.},
journal = {Nutrients},
volume = {16},
number = {8},
pages = {},
pmid = {38674921},
issn = {2072-6643},
mesh = {Humans ; *Carnitine/therapeutic use ; *Nervous System Diseases/drug therapy ; *Mental Disorders/drug therapy ; Dietary Supplements ; },
abstract = {OBJECTIVE: L-carnitine (LC), a vital nutritional supplement, plays a crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application in the recovery and treatment of diverse cardiovascular and cerebrovascular disorders. However, controversies persist regarding the utilization of LC in nervous system diseases, with varying effects observed across numerous mental and neurological disorders. This article primarily aims to gather and analyze database information to comprehensively summarize the therapeutic potential of LC in patients suffering from nervous system diseases while providing valuable references for further research.

METHODS: A comprehensive search was conducted in PubMed, Web Of Science, Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov databases. The literature pertaining to the impact of LC supplementation on neurological or psychiatric disorders in patients was reviewed up until November 2023. No language or temporal restrictions were imposed on the search.

RESULTS: A total of 1479 articles were retrieved, and after the removal of duplicates through both automated and manual exclusion processes, 962 articles remained. Subsequently, a meticulous re-screening led to the identification of 60 relevant articles. Among these, there were 12 publications focusing on hepatic encephalopathy (HE), while neurodegenerative diseases (NDs) and peripheral nervous system diseases (PNSDs) were represented by 9 and 6 articles, respectively. Additionally, stroke was addressed in five publications, whereas Raynaud's syndrome (RS) and cognitive disorder (CD) each had three dedicated studies. Furthermore, migraine, depression, and amyotrophic lateral sclerosis (ALS) each accounted for two publications. Lastly, one article was found for other symptoms under investigation.

CONCLUSION: In summary, LC has demonstrated favorable therapeutic effects in the management of HE, Alzheimer's disease (AD), carpal tunnel syndrome (CTS), CD, migraine, neurofibromatosis (NF), PNSDs, RS, and stroke. However, its efficacy appears to be relatively limited in conditions such as ALS, ataxia, attention deficit hyperactivity disorder (ADHD), depression, chronic fatigue syndrome (CFS), Down syndrome (DS), and sciatica.},
}

Humans
*Carnitine/therapeutic use
*Nervous System Diseases/drug therapy
*Mental Disorders/drug therapy
Dietary Supplements

@article {pmid38674911,
year = {2024},
author = {Fujiwara, K and Tanaka, T and Kobayashi, H and Nagao, K and Ishikawa-Takata, K},
title = {Analysis of the Association between Protein Intake and Disability-Adjusted Life Year Rates for Alzheimer's Disease in Japanese Aged over 60.},
journal = {Nutrients},
volume = {16},
number = {8},
pages = {},
pmid = {38674911},
issn = {2072-6643},
mesh = {Humans ; Female ; Male ; Japan/epidemiology ; Aged ; *Alzheimer Disease/epidemiology ; *Dietary Proteins/administration & dosage ; Middle Aged ; Aged, 80 and over ; *Disability-Adjusted Life Years ; Nutrition Surveys ; Sex Factors ; East Asian People ; },
abstract = {With advancements in medical technology, the structure of disease is shifting from acute illnesses to chronic conditions, such as Alzheimer's disease (AD). Consequently, there is an escalating need for evaluations that discourse on the potential effects on healthy life years, as well as disease onset. We aimed to evaluate the associations with AD disability-adjusted life year (AD-DALY) rates and protein intake by sex and age group. For the analysis, we used representative values for males and females in their 60s and aged over 70, extracted from the public dataset of the Global Burden of Disease Study and the National Health and Nutrition Survey in Japan, covering the years 1990 to 2019. In order to evaluate the association between AD-DALY rates and protein intake, we analyzed correlations and stratified multiple regression models. Additionally, we simulated alterations in AD-DALY rates associated with changes in protein intake by utilizing stratified multiple regression models. AD-DALY rates and protein intake indicated significant negative correlations across all sex and age groups. In stratified multiple regression models, significant associations were found between higher protein intake and lower AD-DALY rates in females. In the simulation, when protein intake was increased to 1.5 g/kg/day, AD-DALY rates decreased by 5-9 percent compared with 2019. However, the association between intake of animal and plant protein and AD-DALY rates were found to vary based on sex and age group. The present study suggests the possibility to improve AD-DALY rates by increasing population average protein intake levels in a recommended range.},
}

Humans
Female
Male
Japan/epidemiology
Aged
*Alzheimer Disease/epidemiology
*Dietary Proteins/administration & dosage
Middle Aged
Aged, 80 and over
*Disability-Adjusted Life Years
Nutrition Surveys
Sex Factors
East Asian People

@article {pmid38674383,
year = {2024},
author = {Sahu, S and Rao, AR and Sahu, TK and Pandey, J and Varshney, S and Kumar, A and Gaikwad, K},
title = {Predictive Role of Cluster Bean (Cyamopsis tetragonoloba) Derived miRNAs in Human and Cattle Health.},
journal = {Genes},
volume = {15},
number = {4},
pages = {},
pmid = {38674383},
issn = {2073-4425},
support = {CRP-Genomics/IX/2017 and F.No. Agril.Edn. 14/2/2017-A&P dated 02.08.2017//ICAR-Consortia Research Platform on Genomics and CABin Scheme Network project on Agricultural Bioinformatics and Computational Biology, received from Indian Council of Agricultural Research (ICAR)./ ; },
mesh = {Cattle ; Animals ; *MicroRNAs/genetics ; Humans ; Cyamopsis/genetics ; RNA, Plant/genetics ; Cattle Diseases/genetics ; },
abstract = {MicroRNAs (miRNAs) are small non-coding conserved molecules with lengths varying between 18-25nt. Plants miRNAs are very stable, and probably they might have been transferred across kingdoms via food intake. Such miRNAs are also called exogenous miRNAs, which regulate the gene expression in host organisms. The miRNAs present in the cluster bean, a drought tolerant legume crop having high commercial value, might have also played a regulatory role for the genes involved in nutrients synthesis or disease pathways in animals including humans due to dietary intake of plant parts of cluster beans. However, the predictive role of miRNAs of cluster beans for gene-disease association across kingdoms such as cattle and humans are not yet fully explored. Thus, the aim of the present study is to (i) find out the cluster bean miRNAs (cb-miRs) functionally similar to miRNAs of cattle and humans and predict their target genes' involvement in the occurrence of complex diseases, and (ii) identify the role of cb-miRs that are functionally non-similar to the miRNAs of cattle and humans and predict their targeted genes' association with complex diseases in host systems. Here, we predicted a total of 33 and 15 functionally similar cb-miRs (fs-cb-miRs) to human and cattle miRNAs, respectively. Further, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the participation of targeted genes of fs-cb-miRs in 24 and 12 different pathways in humans and cattle, respectively. Few targeted genes in humans like LCP2, GABRA6, and MYH14 were predicted to be associated with disease pathways of Yesinia infection (hsa05135), neuroactive ligand-receptor interaction (hsa04080), and pathogenic Escherichia coli infection (hsa05130), respectively. However, targeted genes of fs-cb-miRs in humans like KLHL20, TNS1, and PAPD4 are associated with Alzheimer's, malignant tumor of the breast, and hepatitis C virus infection disease, respectively. Similarly, in cattle, targeted genes like ATG2B and DHRS11 of fs-cb-miRs participate in the pathways of Huntington disease and steroid biosynthesis, respectively. Additionally, the targeted genes like SURF4 and EDME2 of fs-cb-miRs are associated with mastitis and bovine osteoporosis, respectively. We also found a few cb-miRs that do not have functional similarity with human and cattle miRNAs but are found to target the genes in the host organisms and as well being associated with human and cattle diseases. Interestingly, a few genes such as NRM, PTPRE and SUZ12 were observed to be associated with Rheumatoid Arthritis, Asthma and Endometrial Stromal Sarcoma diseases, respectively, in humans and genes like SCNN1B associated with renal disease in cattle.},
}

Cattle
Animals
*MicroRNAs/genetics
Humans
Cyamopsis/genetics
RNA, Plant/genetics
Cattle Diseases/genetics

@article {pmid38674351,
year = {2024},
author = {Picard, C and Miron, J and Poirier, J},
title = {Association of TMEM106B with Cortical APOE Gene Expression in Neurodegenerative Conditions.},
journal = {Genes},
volume = {15},
number = {4},
pages = {},
pmid = {38674351},
issn = {2073-4425},
support = {#PJT 153287 & PJT 178210/CAPMC/CIHR/Canada ; },
mesh = {*Membrane Proteins/genetics/metabolism ; Humans ; Animals ; Mice ; *Alzheimer Disease/genetics/metabolism/pathology ; *Nerve Tissue Proteins/genetics/metabolism ; Apolipoproteins E/genetics ; Male ; Female ; Neurodegenerative Diseases/genetics/metabolism ; Hippocampus/metabolism ; Aged ; Genome-Wide Association Study ; Disease Models, Animal ; },
abstract = {The e4 allele of the apolipoprotein E gene is the strongest genetic risk factor for sporadic Alzheimer's disease. Nevertheless, how APOE is regulated is still elusive. In a trans-eQTL analysis, we found a genome-wide significant association between transmembrane protein 106B (TMEM106B) genetic variants and cortical APOE mRNA levels in human brains. The goal of this study is to determine whether TMEM106B is mis-regulated in Alzheimer's disease or in other neurodegenerative conditions. Available genomic, transcriptomic and proteomic data from human brains were downloaded from the Mayo Clinic Brain Bank and the Religious Orders Study and Memory and Aging Project. An in-house mouse model of the hippocampal deafferentation/reinnervation was achieved via a stereotaxic lesioning surgery to the entorhinal cortex, and mRNA levels were measured using RNAseq technology. In human temporal cortices, the mean TMEM106B expression was significantly higher in Alzheimer's disease compared to cognitively unimpaired individuals. In the mouse model, hippocampal Tmem106b reached maximum levels during the early phase of reinnervation. These results suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling.},
}

*Membrane Proteins/genetics/metabolism
Humans
Animals
Mice
*Alzheimer Disease/genetics/metabolism/pathology
*Nerve Tissue Proteins/genetics/metabolism
Apolipoproteins E/genetics
Male
Female
Neurodegenerative Diseases/genetics/metabolism
Hippocampus/metabolism
Aged
Genome-Wide Association Study
Disease Models, Animal

@article {pmid38674233,
year = {2024},
author = {Trišins, M and Zdanovskis, N and Platkājis, A and Šneidere, K and Kostiks, A and Karelis, G and Stepens, A},
title = {Brodmann Areas, V1 Atlas and Cognitive Impairment: Assessing Cortical Thickness for Cognitive Impairment Diagnostics.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {60},
number = {4},
pages = {},
pmid = {38674233},
issn = {1648-9144},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Cross-Sectional Studies ; *Magnetic Resonance Imaging/methods ; Aged ; Middle Aged ; *Cerebral Cortex/diagnostic imaging/pathology ; Mental Status and Dementia Tests/statistics & numerical data ; Brain Cortical Thickness ; },
abstract = {Background and Objectives: Magnetic resonance imaging is vital for diagnosing cognitive decline. Brodmann areas (BA), distinct regions of the cerebral cortex categorized by cytoarchitectural variances, provide insights into cognitive function. This study aims to compare cortical thickness measurements across brain areas identified by BA mapping. We assessed these measurements among patients with and without cognitive impairment, and across groups categorized by cognitive performance levels using the Montreal Cognitive Assessment (MoCA) test. Materials and Methods: In this cross-sectional study, we included 64 patients who were divided in two ways: in two groups with (CI) or without (NCI) impaired cognitive function and in three groups with normal (NC), moderate (MPG) and low (LPG) cognitive performance according to MoCA scores. Scans with a 3T MRI scanner were carried out, and cortical thickness data was acquired using Freesurfer 7.2.0 software. Results: By analyzing differences between the NCI and CI groups cortical thickness of BA3a in left hemisphere (U = 241.000, p = 0.016), BA4a in right hemisphere (U = 269.000, p = 0.048) and BA28 in left hemisphere (U = 584.000, p = 0.005) showed significant differences. In the LPG, MPG and NC cortical thickness in BA3a in left hemisphere (H (2) = 6.268, p = 0.044), in V2 in right hemisphere (H (2) = 6.339, p = 0.042), in BA28 in left hemisphere (H (2) = 23.195, p < 0.001) and in BA28 in right hemisphere (H (2) = 10.015, p = 0.007) showed significant differences. Conclusions: Our study found that cortical thickness in specific Brodmann Areas-BA3a and BA28 in the left hemisphere, and BA4a in the right-differ significantly between NCI and CI groups. Significant differences were also observed in BA3a (left), V2 (right), and BA28 (both hemispheres) across LPG, MPG, NC groups. Despite a small sample size, these findings suggest cortical thickness measurements can serve as effective biomarkers for cognitive impairment diagnosis, warranting further validation with a larger cohort.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Cross-Sectional Studies
*Magnetic Resonance Imaging/methods
Aged
Middle Aged
*Cerebral Cortex/diagnostic imaging/pathology
Mental Status and Dementia Tests/statistics & numerical data
Brain Cortical Thickness

@article {pmid38674150,
year = {2024},
author = {Ramos, R and Vale, N},
title = {Dual Drug Repurposing: The Example of Saracatinib.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
pmid = {38674150},
issn = {1422-0067},
mesh = {Humans ; *Drug Repositioning/methods ; *Quinazolines/therapeutic use/chemistry/pharmacology ; *Benzodioxoles/therapeutic use/chemistry/pharmacology ; Animals ; Protein Kinase Inhibitors/therapeutic use/chemistry/pharmacology/adverse effects ; Alzheimer Disease/drug therapy ; src-Family Kinases/antagonists & inhibitors/metabolism ; Neoplasms/drug therapy ; Antineoplastic Agents/therapeutic use/chemistry ; },
abstract = {Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer's disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases.},
}

Humans
*Drug Repositioning/methods
*Quinazolines/therapeutic use/chemistry/pharmacology
*Benzodioxoles/therapeutic use/chemistry/pharmacology
Animals
Protein Kinase Inhibitors/therapeutic use/chemistry/pharmacology/adverse effects
Alzheimer Disease/drug therapy
src-Family Kinases/antagonists & inhibitors/metabolism
Neoplasms/drug therapy
Antineoplastic Agents/therapeutic use/chemistry

@article {pmid38674097,
year = {2024},
author = {Lewitt, MS and Boyd, GW},
title = {Role of the Insulin-like Growth Factor System in Neurodegenerative Disease.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
pmid = {38674097},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/metabolism/genetics ; Alzheimer Disease/metabolism/genetics/etiology/pathology ; Signal Transduction ; Insulin-Like Growth Factor I/metabolism/genetics ; Somatomedins/metabolism ; Disease Models, Animal ; Parkinson Disease/metabolism/genetics ; Insulin-Like Growth Factor Binding Proteins/metabolism/genetics ; Insulin-Like Peptides ; },
abstract = {The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.},
}

Humans
Animals
*Neurodegenerative Diseases/metabolism/genetics
Alzheimer Disease/metabolism/genetics/etiology/pathology
Signal Transduction
Insulin-Like Growth Factor I/metabolism/genetics
Somatomedins/metabolism
Disease Models, Animal
Parkinson Disease/metabolism/genetics
Insulin-Like Growth Factor Binding Proteins/metabolism/genetics
Insulin-Like Peptides

@article {pmid38674094,
year = {2024},
author = {Elashiry, M and Carroll, A and Yuan, J and Liu, Y and Hamrick, M and Cutler, CW and Wang, Q and Elsayed, R},
title = {Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood-Brain Barrier.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
pmid = {38674094},
issn = {1422-0067},
mesh = {*Blood-Brain Barrier/metabolism ; Animals ; Humans ; Mice ; *Extracellular Vesicles/metabolism ; *Porphyromonas gingivalis/metabolism/pathogenicity ; *Periodontitis/microbiology/metabolism/pathology ; *Gingiva/metabolism/microbiology ; Mice, Inbred C57BL ; Male ; Exosomes/metabolism ; Female ; Bacteroidaceae Infections/microbiology/metabolism ; },
abstract = {Porphyromonas gingivalis (Pg) and its gingipain proteases contribute to Alzheimer's disease (AD) pathogenesis through yet unclear mechanisms. Cellular secretion of small extracellular vesicles or exosomes (EXO) increases with aging as part of the senescence-associated secretory phenotype (SASP). We have shown that EXO isolated from Pg-infected dendritic cells contain gingipains and other Pg antigens and transmit senescence to bystander gingival cells, inducing alveolar bone loss in mice in vivo. Here, EXO were isolated from the gingiva of mice and humans with/without periodontitis (PD) to determine their ability to penetrate the blood-brain barrier (BBB) in vitro and in vivo. PD was induced by Pg oral gavage for 6 weeks in C57B6 mice. EXO isolated from the gingiva or brain of donor Pg-infected (PD EXO) or control animals (Con EXO) were characterized by NTA, Western blot, and TEM. Gingival PD EXO or Con EXO were labeled and injected into the gingiva of uninfected WT mouse model. EXO biodistribution in brains was tracked by an in vivo imaging system (IVIS) and confocal microscopy. The effect of human PD EXO on BBB integrity and permeability was examined using TEER and FITC dextran assays in a human in vitro 3D model of the BBB. Pg antigens (RGP and Mfa-1) were detected in EXO derived from gingival and brain tissues of donor Pg-infected mice. Orally injected PD EXO from donor mice penetrated the brains of recipient uninfected mice and colocalized with hippocampal microglial cells. IL-1β and IL-6 were expressed in human PD EXO and not in Con EXO. Human PD EXO promoted BBB permeability and penetrated the BBB in vitro. This is the first demonstration that microbial-induced EXO in the oral cavity can disseminate, cross the BBB, and may contribute to AD pathogenesis.},
}

*Blood-Brain Barrier/metabolism
Animals
Humans
Mice
*Extracellular Vesicles/metabolism
*Porphyromonas gingivalis/metabolism/pathogenicity
*Periodontitis/microbiology/metabolism/pathology
*Gingiva/metabolism/microbiology
Mice, Inbred C57BL
Male
Exosomes/metabolism
Female
Bacteroidaceae Infections/microbiology/metabolism

@article {pmid38674088,
year = {2024},
author = {Plachokova, AS and Gjaltema, J and Hagens, ERC and Hashemi, Z and Knüppe, TBA and Kootstra, TJM and Visser, A and Bloem, BR},
title = {Periodontitis: A Plausible Modifiable Risk Factor for Neurodegenerative Diseases? A Comprehensive Review.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
pmid = {38674088},
issn = {1422-0067},
mesh = {Humans ; *Periodontitis/complications/epidemiology ; Risk Factors ; *Neurodegenerative Diseases/epidemiology/etiology ; Parkinson Disease/epidemiology ; Alzheimer Disease/etiology/epidemiology ; },
abstract = {The aim of this comprehensive review is to summarize recent literature on associations between periodontitis and neurodegenerative diseases, explore the bidirectionality and provide insights into the plausible pathogenesis. For this purpose, systematic reviews and meta-analyses from PubMed, Medline and EMBASE were considered. Out of 33 retrieved papers, 6 articles complying with the inclusion criteria were selected and discussed. Additional relevant papers for bidirectionality and pathogenesis were included. Results show an association between periodontitis and Alzheimer's disease, with odds ratios of 3 to 5. A bidirectional relationship is suspected. For Parkinson's disease (PD), current evidence for an association appears to be weak, although poor oral health and PD seem to be correlated. A huge knowledge gap was identified. The plausible mechanistic link for the association between periodontitis and neurodegenerative diseases is the interplay between periodontal inflammation and neuroinflammation. Three pathways are hypothesized in the literature, i.e., humoral, neuronal and cellular, with a clear role of periodontal pathogens, such as Porphyromonas gingivalis. Age, gender, race, smoking, alcohol intake, nutrition, physical activity, socioeconomic status, stress, medical comorbidities and genetics were identified as common risk factors for periodontitis and neurodegenerative diseases. Future research with main emphasis on the collaboration between neurologists and dentists is encouraged.},
}

Humans
*Periodontitis/complications/epidemiology
Risk Factors
*Neurodegenerative Diseases/epidemiology/etiology
Parkinson Disease/epidemiology
Alzheimer Disease/etiology/epidemiology

@article {pmid38674050,
year = {2024},
author = {Choi, YK},
title = {Detrimental Roles of Hypoxia-Inducible Factor-1α in Severe Hypoxic Brain Diseases.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
pmid = {38674050},
issn = {1422-0067},
support = {2023//This paper was supported by Konkuk University in 2023/ ; },
mesh = {Humans ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Animals ; Hypoxia, Brain/metabolism ; Oxidative Stress ; Mitochondria/metabolism ; Alzheimer Disease/metabolism/pathology ; Brain/metabolism/pathology ; },
abstract = {Hypoxia stabilizes hypoxia-inducible factors (HIFs), facilitating adaptation to hypoxic conditions. Appropriate hypoxia is pivotal for neurovascular regeneration and immune cell mobilization. However, in central nervous system (CNS) injury, prolonged and severe hypoxia harms the brain by triggering neurovascular inflammation, oxidative stress, glial activation, vascular damage, mitochondrial dysfunction, and cell death. Diminished hypoxia in the brain improves cognitive function in individuals with CNS injuries. This review discusses the current evidence regarding the contribution of severe hypoxia to CNS injuries, with an emphasis on HIF-1α-mediated pathways. During severe hypoxia in the CNS, HIF-1α facilitates inflammasome formation, mitochondrial dysfunction, and cell death. This review presents the molecular mechanisms by which HIF-1α is involved in the pathogenesis of CNS injuries, such as stroke, traumatic brain injury, and Alzheimer's disease. Deciphering the molecular mechanisms of HIF-1α will contribute to the development of therapeutic strategies for severe hypoxic brain diseases.},
}

Humans
*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
Animals
Hypoxia, Brain/metabolism
Oxidative Stress
Mitochondria/metabolism
Alzheimer Disease/metabolism/pathology
Brain/metabolism/pathology

@article {pmid38673909,
year = {2024},
author = {Liu, Z and Chen, Y and Chen, Y and Zheng, J and Wu, W and Wang, L and Wang, H and Yu, Y},
title = {Effect of Regulation of Chemerin/Chemokine-like Receptor 1/Stimulator of Interferon Genes Pathway on Astrocyte Recruitment to Aβ Plaques.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
pmid = {38673909},
issn = {1422-0067},
support = {22ZR1434700//Natural Science Foundation of Shanghai/ ; 81870835//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Astrocytes/metabolism ; *Chemokines/metabolism ; *Intercellular Signaling Peptides and Proteins/metabolism/genetics ; Mice ; *Receptors, Chemokine/metabolism/genetics ; *Plaque, Amyloid/metabolism/pathology ; *Alzheimer Disease/metabolism/genetics/pathology ; Humans ; Amyloid beta-Peptides/metabolism ; Mice, Knockout ; Cell Movement ; Signal Transduction ; Mice, Transgenic ; Mice, Inbred C57BL ; },
abstract = {Recruitment and accumulation of reactive astrocytes around senile plaques are common pathological features of Alzheimer's disease (AD), with unclear mechanisms. Chemerin, an adipokine implicated in neuroinflammation, acts through its receptor, chemokine-like receptor 1 (CMKLR1), which also functions as a receptor for amyloid β (Aβ). The impact of the chemerin/CMKLR1 axis on astrocyte migration towards Aβ plaques is unknown. Here we investigated the effect of CMKLR1 on astrocyte migration around Aβ deposition in APP/PS1 mice with Cmklr1 knockout (APP/PS1-Cmklr1[-/-]). CMKLR1-expressed astrocytes were upregulated in the cortices and hippocampi of 9-month-old APP/PS1 mice. Chemerin mainly co-localized with neurons, and its expression was reduced in the brains of APP/PS1 mice, compared to WT mice. CMKLR1 deficiency decreased astrocyte colocalization with Aβ plaques in APP/PS1-Cmklr1[-/-] mice, compared to APP/PS1 mice. Activation of the chemerin/CMKLR1 axis promoted the migration of primary cultured astrocytes and U251 cells, and reduced astrocyte clustering induced by Aβ42. Mechanistic studies revealed that chemerin/CMKLR1 activation induced STING phosphorylation. Deletion of STING attenuated the promotion of the chemerin/CMKLR1 axis relative to astrocyte migration and abolished the inhibitory effect of chemerin on Aβ42-induced astrocyte clustering. These findings suggest the involvement of the chemerin/CMKLR1/STING pathway in the regulation of astrocyte migration and recruitment to Aβ plaques/Aβ42.},
}

Animals
*Astrocytes/metabolism
*Chemokines/metabolism
*Intercellular Signaling Peptides and Proteins/metabolism/genetics
Mice
*Receptors, Chemokine/metabolism/genetics
*Plaque, Amyloid/metabolism/pathology
*Alzheimer Disease/metabolism/genetics/pathology
Humans
Amyloid beta-Peptides/metabolism
Mice, Knockout
Cell Movement
Signal Transduction
Mice, Transgenic
Mice, Inbred C57BL

@article {pmid38673907,
year = {2024},
author = {Agnello, L and Gambino, CM and Ciaccio, AM and Masucci, A and Vassallo, R and Tamburello, M and Scazzone, C and Lo Sasso, B and Ciaccio, M},
title = {Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
doi = {10.3390/ijms25084323},
pmid = {38673907},
issn = {1422-0067},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Neurodegenerative Diseases/diagnosis/cerebrospinal fluid/metabolism ; Alzheimer Disease/diagnosis/cerebrospinal fluid/metabolism/genetics ; },
abstract = {Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death of the nervous system's cells. The diagnosis is challenging, especially in the early stages, due to no specific clinical signs and symptoms. In this context, laboratory medicine could support clinicians in detecting and differentiating NDs. Indeed, biomarkers could indicate the pathological mechanisms underpinning NDs. The ideal biofluid for detecting the biomarkers of NDs is cerebrospinal fluid (CSF), which has limitations, hampering its widespread use in clinical practice. However, intensive efforts are underway to introduce high-sensitivity analytical methods to detect ND biomarkers in alternative nonivasive biofluid, such as blood or saliva. This study presents an overview of the ND molecular biomarkers currently used in clinical practice. For some diseases, such as Alzheimer's disease or multiple sclerosis, biomarkers are well established and recommended by guidelines. However, for most NDs, intensive research is ongoing to identify reliable and specific biomarkers, and no consensus has yet been achieved.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Neurodegenerative Diseases/diagnosis/cerebrospinal fluid/metabolism
Alzheimer Disease/diagnosis/cerebrospinal fluid/metabolism/genetics

@article {pmid38673848,
year = {2024},
author = {Pérez Gutiérrez, RM and Rodríguez-Serrano, LM and Laguna-Chimal, JF and de la Luz Corea, M and Paredes Carrera, SP and Téllez Gomez, J},
title = {Geniposide and Harpagoside Functionalized Cerium Oxide Nanoparticles as a Potential Neuroprotective.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
doi = {10.3390/ijms25084262},
pmid = {38673848},
issn = {1422-0067},
mesh = {*Cerium/chemistry/pharmacology ; *Iridoids/pharmacology/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Mice ; *Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Nanoparticles/chemistry ; Metal Nanoparticles/chemistry ; Disease Models, Animal ; },
abstract = {Alzheimer's disease is associated with protein aggregation, oxidative stress, and the role of acetylcholinesterase in the pathology of the disease. Previous investigations have demonstrated that geniposide and harpagoside protect the brain neurons, and cerium nanoparticles (CeO2 NPs) have potent redox and antioxidant properties. Thus, the effect of nanoparticles of Ce NPs and geniposide and harpagoside (GH/CeO2 NPs) on ameliorating AD pathogenesis was established on AlCl3-induced AD in mice and an aggregation proteins test in vitro. Findings of spectroscopy analysis have revealed that GH/CeO2 NPs are highly stable, nano-size, spherical in shape, amorphous nature, and a total encapsulation of GH in cerium. Treatments with CeO2 NPs, GH/CeO2 NPs, and donepezil used as positive control inhibit fibril formation and protein aggregation, protect structural modifications in the BSA-ribose system, have the ability to counteract Tau protein aggregation and amyloid-β1-42 aggregation under fibrillation condition, and are able to inhibit AChE and BuChE. While the GH/CeO2 NPs, treatment in AD induced by AlCl3 inhibited amyloid-β1-42, substantially enhanced the memory, the cognition coordination of movement in part AD pathogenesis may be alleviated through reducing amyloidogenic pathway and AChE and BuChE activities. The findings of this work provide important comprehension of the chemoprotective activities of iridoids combined with nanoparticles. This could be useful in the development of new therapeutic methods for the treatment of neurodegenerative diseases.},
}

*Cerium/chemistry/pharmacology
*Iridoids/pharmacology/chemistry
Animals
*Neuroprotective Agents/pharmacology/chemistry
Mice
*Alzheimer Disease/drug therapy/metabolism
*Acetylcholinesterase/metabolism
Amyloid beta-Peptides/metabolism
Male
Nanoparticles/chemistry
Metal Nanoparticles/chemistry
Disease Models, Animal

@article {pmid38673819,
year = {2024},
author = {Paveliev, M and Egorchev, AA and Musin, F and Lipachev, N and Melnikova, A and Gimadutdinov, RM and Kashipov, AR and Molotkov, D and Chickrin, DE and Aganov, AV},
title = {Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
doi = {10.3390/ijms25084227},
pmid = {38673819},
issn = {1422-0067},
mesh = {Humans ; *Artificial Intelligence ; *Brain/pathology/diagnostic imaging ; *Extracellular Matrix/metabolism ; Animals ; Microscopy/methods ; Nerve Net/pathology ; Synapses/pathology ; Brain Diseases/pathology ; Neurons/pathology/metabolism ; },
abstract = {Perineuronal nets (PNN) are a special highly structured type of extracellular matrix encapsulating synapses on large populations of CNS neurons. PNN undergo structural changes in schizophrenia, epilepsy, Alzheimer's disease, stroke, post-traumatic conditions, and some other brain disorders. The functional role of the PNN microstructure in brain pathologies has remained largely unstudied until recently. Here, we review recent research implicating PNN microstructural changes in schizophrenia and other disorders. We further concentrate on high-resolution studies of the PNN mesh units surrounding synaptic boutons to elucidate fine structural details behind the mutual functional regulation between the ECM and the synaptic terminal. We also review some updates regarding PNN as a potential pharmacological target. Artificial intelligence (AI)-based methods are now arriving as a new tool that may have the potential to grasp the brain's complexity through a wide range of organization levels-from synaptic molecular events to large scale tissue rearrangements and the whole-brain connectome function. This scope matches exactly the complex role of PNN in brain physiology and pathology processes, and the first AI-assisted PNN microscopy studies have been reported. To that end, we report here on a machine learning-assisted tool for PNN mesh contour tracing.},
}

Humans
*Artificial Intelligence
*Brain/pathology/diagnostic imaging
*Extracellular Matrix/metabolism
Animals
Microscopy/methods
Nerve Net/pathology
Synapses/pathology
Brain Diseases/pathology
Neurons/pathology/metabolism

@article {pmid38673816,
year = {2024},
author = {Gutiérrez-Hurtado, IA and Sánchez-Méndez, AD and Becerra-Loaiza, DS and Rangel-Villalobos, H and Torres-Carrillo, N and Gallegos-Arreola, MP and Aguilar-Velázquez, JA},
title = {Loss of the Y Chromosome: A Review of Molecular Mechanisms, Age Inference, and Implications for Men's Health.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
doi = {10.3390/ijms25084230},
pmid = {38673816},
issn = {1422-0067},
mesh = {Humans ; *Chromosomes, Human, Y/genetics ; Male ; *Men's Health ; Aging/genetics ; Mosaicism ; Chromosome Deletion ; },
abstract = {Until a few years ago, it was believed that the gradual mosaic loss of the Y chromosome (mLOY) was a normal age-related process. However, it is now known that mLOY is associated with a wide variety of pathologies in men, such as cardiovascular diseases, neurodegenerative disorders, and many types of cancer. Nevertheless, the mechanisms that generate mLOY in men have not been studied so far. This task is of great importance because it will allow focusing on possible methods of prophylaxis or therapy for diseases associated with mLOY. On the other hand, it would allow better understanding of mLOY as a possible marker for inferring the age of male samples in cases of human identification. Due to the above, in this work, a comprehensive review of the literature was conducted, presenting the most relevant information on the possible molecular mechanisms by which mLOY is generated, as well as its implications for men's health and its possible use as a marker to infer age.},
}

Humans
*Chromosomes, Human, Y/genetics
Male
*Men's Health
Aging/genetics
Mosaicism
Chromosome Deletion

@article {pmid38673751,
year = {2024},
author = {Kiss, E and Kins, S and Gorgas, K and Venczel Szakács, KH and Kirsch, J and Kuhse, J},
title = {Another Use for a Proven Drug: Experimental Evidence for the Potential of Artemisinin and Its Derivatives to Treat Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {25},
number = {8},
pages = {},
doi = {10.3390/ijms25084165},
pmid = {38673751},
issn = {1422-0067},
support = {PN-III-P4-PCE-2021-1089//Romanian Ministry of Research and Innovation CNCS- UEFISCDI/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Artemisinins/therapeutic use/pharmacology/chemistry ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Apoptosis/drug effects ; },
abstract = {Plant-derived multitarget compounds may represent a promising therapeutic strategy for multifactorial diseases, such as Alzheimer's disease (AD). Artemisinin and its derivatives were indicated to beneficially modulate various aspects of AD pathology in different AD animal models through the regulation of a wide range of different cellular processes, such as energy homeostasis, apoptosis, proliferation and inflammatory pathways. In this review, we aimed to provide an up-to-date overview of the experimental evidence documenting the neuroprotective activities of artemi-sinins to underscore the potential of these already-approved drugs for treating AD also in humans and propose their consideration for carefully designed clinical trials. In particular, the benefits to the main pathological hallmarks and events in the pathological cascade throughout AD development in different animal models of AD are summarized. Moreover, dose- and context-dependent effects of artemisinins are noted.},
}

*Alzheimer Disease/drug therapy/metabolism
*Artemisinins/therapeutic use/pharmacology/chemistry
Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
Disease Models, Animal
Apoptosis/drug effects

@article {pmid38673657,
year = {2024},
author = {Tyczyńska, M and Gędek, M and Brachet, A and Stręk, W and Flieger, J and Teresiński, G and Baj, J},
title = {Trace Elements in Alzheimer's Disease and Dementia: The Current State of Knowledge.},
journal = {Journal of clinical medicine},
volume = {13},
number = {8},
pages = {},
doi = {10.3390/jcm13082381},
pmid = {38673657},
issn = {2077-0383},
support = {DS707//Medical University of Lublin/ ; },
abstract = {Changes in trace element concentrations are being wildly considered when it comes to neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. This study aims to present the role that trace elements play in the central nervous system. Moreover, we reviewed the mechanisms involved in their neurotoxicity. Low zinc concentrations, as well as high levels of copper, manganese, and iron, activate the signalling pathways of the inflammatory, oxidative and nitrosative stress response. Neurodegeneration occurs due to the association between metals and proteins, which is then followed by aggregate formation, mitochondrial disorder, and, ultimately, cell death. In Alzheimer's disease, low Zn levels suppress the neurotoxicity induced by β-amyloid through the selective precipitation of aggregation intermediates. High concentrations of copper, iron and manganese cause the aggregation of intracellular α-synuclein, which results in synaptic dysfunction and axonal transport disruption. Parkinson's disease is caused by the accumulation of Fe in the midbrain dopaminergic nucleus, and the pathogenesis of multiple sclerosis derives from Zn deficiency, leading to an imbalance between T cell functions. Aluminium disturbs the homeostasis of other metals through a rise in the production of oxygen reactive forms, which then leads to cellular death. Selenium, in association with iron, plays a distinct role in the process of ferroptosis. Outlining the influence that metals have on oxidoreduction processes is crucial to recognising the pathophysiology of neurodegenerative diseases and may provide possible new methods for both their avoidance and therapy.},
}

@article {pmid38673594,
year = {2024},
author = {Ponsoda, JM and Díaz, A},
title = {Positive Emotions in Family Caregivers of Alzheimer's Disease Patients: Factors Associated with Gain in Caregiving from a Gender Perspective.},
journal = {Journal of clinical medicine},
volume = {13},
number = {8},
pages = {},
doi = {10.3390/jcm13082322},
pmid = {38673594},
issn = {2077-0383},
abstract = {Background/Objectives: Gender differences in the variables of burden, anxiety, depression, and others associated with psychological distress have been found in studies on caregivers caring for a dependent relative, but a gender perspective is seldom used when analysing the positive aspects of caregiving. This study contributes to filling this gap by analysing gender differences in caregivers in a specific positive variable: gain. Methods: A cross-sectional design was used in a sample of 44 male and 96 female caregivers from Family Alzheimer Associations. Gender differences were analysed in demographic and psychological variables associated with the caregiving situation. Results: Female caregivers showed higher psychological distress than male caregivers, but gender differences in gain were only obvious when a deeper analysis of the GAIN scale responses was performed. The mediational role of psychological distress and other predictive variables showed a different pattern in male and female caregivers. The important predictive and mediating role that psychological distress plays in the greater perception of gains in caregiving and the result showing that female caregivers are the ones with poorer mental health support the need for preventive and therapeutic programs specifically targeting the positive aspects of caregiving in female caregivers. Conclusions: Three aspects could be highlighted in this study: family caregivers of AD patients perceived gain in the caregiving situation; gender plays a differential role in the perception of gain; and, finally, psychological distress should be the target when interventions are planned, not only to alleviate negative aspects but also to increase the positive aspects of caregiving.},
}

@article {pmid38673407,
year = {2024},
author = {Niu, X and Chang, J and Corrada, MM and Bullock, A and Winchester, B and Manson, SM and O'Connell, J and Jiang, L},
title = {The Relationship between All-Cause Dementia and Acute Diabetes Complications among American Indian and Alaska Native Peoples.},
journal = {International journal of environmental research and public health},
volume = {21},
number = {4},
pages = {},
doi = {10.3390/ijerph21040496},
pmid = {38673407},
issn = {1660-4601},
support = {R01AG061189/AG/NIA NIH HHS/United States ; R18DK114757/DK/NIDDK NIH HHS/United States ; P30DK092923/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; *Dementia/epidemiology ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Alaska Natives/statistics & numerical data ; Aged ; *Indians, North American/statistics & numerical data ; *Diabetes Complications/epidemiology ; United States/epidemiology ; Aged, 80 and over ; },
abstract = {BACKGROUND: American Indian and Alaska Native people (AI/AN) bear a disproportionate burden of diabetes. Growing evidence shows significant associations between several acute diabetes complications and dementia among diabetes patients. However, little is known about these relationships among AI/AN adults. Here, we aim to investigate these associations among AI/AN adults.

METHODS: This cross-sectional study extracted data from the Indian Health Service's (IHS) National Data Warehouse and related administrative databases. A total of 29,337 IHS actual users with diabetes who were 45+ years old during fiscal year 2013 were included. All-cause dementia and diabetes complications were identified using ICD-9 diagnostic codes. Negative binomial regression models were used to evaluate the associations of interest.

RESULTS: Nearly 3% of AI/AN diabetes patients had a dementia diagnosis. After controlling for covariates, dementia was associated with a 94% higher rate of severe hypoglycemia (Incidence Rate Ratio [IRR = 1.94, 95% CI:1.50-2.51), 52% higher rate of severe hyperglycemia (IRR = 1.52, 95% CI, 1.11-2.08), and 92% higher rate of any acute complication (IRR = 1.92, 95% CI:1.53-2.41).

CONCLUSIONS: AI/AN diabetes patients with dementia suffered from considerably higher rates of acute diabetes complications than their counterparts without dementia. The clinical management of patients with comorbid diabetes and dementia is particularly challenging and may require individualized treatment approaches.},
}

Humans
*Dementia/epidemiology
Male
Female
Middle Aged
Cross-Sectional Studies
*Alaska Natives/statistics & numerical data
Aged
*Indians, North American/statistics & numerical data
*Diabetes Complications/epidemiology
United States/epidemiology
Aged, 80 and over

@article {pmid38673396,
year = {2024},
author = {Santonja-Ayuso, L and Corchón-Arreche, S and Portillo, MC},
title = {Interventions to Foster Resilience in Family Caregivers of People with Alzheimer's Disease: A Scoping Review.},
journal = {International journal of environmental research and public health},
volume = {21},
number = {4},
pages = {},
doi = {10.3390/ijerph21040485},
pmid = {38673396},
issn = {1660-4601},
support = {2021_02//nursing college of valencia/ ; },
mesh = {*Alzheimer Disease/psychology/nursing ; *Caregivers/psychology ; Humans ; *Resilience, Psychological ; },
abstract = {The family caregiver of a person with Alzheimer's disease still experiences, in most cases, negative consequences in their biopsychosocial environment, which are related to the acquisition of this role. However, it has been observed that this fact is not universal in this type of population since benefits can be obtained in the act of caring through the development of resilience. Given this possibility and given that nurses are the health professionals who support people in this illness process, there is an urgent need to identify which non-pharmacological interventions could improve or promote resilience in family caregivers of people with Alzheimer's disease. Therefore, our overall objective was to determine which interventions are useful in promoting resilience in family caregivers of people with Alzheimer's disease through a scoping review. The data were analysed using an adapted version of Arksey and O'Malley's methodological framework, after critically reading the articles with the CasP and MMAT tools. Nine articles were included (five analytical experimental, two quantitative and two mixed). Three types of interventions related to promoting resilience in family caregivers of people with Alzheimer's disease were identified: meditation, multicomponent psychoeducation and creative art; nurses participated as co-therapists in the last two.},
}

*Alzheimer Disease/psychology/nursing
*Caregivers/psychology
Humans
*Resilience, Psychological

@article {pmid38673048,
year = {2024},
author = {Machado Reyes, D and Chao, H and Hahn, J and Shen, L and Yan, P and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {Identifying Progression-Specific Alzheimer's Subtypes Using Multimodal Transformer.},
journal = {Journal of personalized medicine},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/jpm14040421},
pmid = {38673048},
issn = {2075-4426},
support = {T32AG078123/AG/NIA NIH HHS/United States ; AG066833/NH/NIH HHS/United States ; AG068057/NH/NIH HHS/United States ; AG063481/NH/NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet its current treatments are limited to stopping disease progression. Moreover, the effectiveness of these treatments remains uncertain due to the heterogeneity of the disease. Therefore, it is essential to identify disease subtypes at a very early stage. Current data-driven approaches can be used to classify subtypes during later stages of AD or related disorders, but making predictions in the asymptomatic or prodromal stage is challenging. Furthermore, the classifications of most existing models lack explainability, and these models rely solely on a single modality for assessment, limiting the scope of their analysis. Thus, we propose a multimodal framework that utilizes early-stage indicators, including imaging, genetics, and clinical assessments, to classify AD patients into progression-specific subtypes at an early stage. In our framework, we introduce a tri-modal co-attention mechanism (Tri-COAT) to explicitly capture cross-modal feature associations. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (slow progressing = 177, intermediate = 302, and fast = 15) were used to train and evaluate Tri-COAT using a 10-fold stratified cross-testing approach. Our proposed model outperforms baseline models and sheds light on essential associations across multimodal features supported by known biological mechanisms. The multimodal design behind Tri-COAT allows it to achieve the highest classification area under the receiver operating characteristic curve while simultaneously providing interpretability to the model predictions through the co-attention mechanism.},
}

@article {pmid38672954,
year = {2024},
author = {Jabeen, R and Jan, N and Naseer, B and Sarangi, PK and Sridhar, K and Dikkala, PK and Bhaswant, M and Hussain, SZ and Inbaraj, BS},
title = {Development of Germinated-Brown-Rice-Based Novel Functional Beverage Enriched with γ-Aminobutyric Acid: Nutritional and Bio-Functional Characterization.},
journal = {Foods (Basel, Switzerland)},
volume = {13},
number = {8},
pages = {},
doi = {10.3390/foods13081282},
pmid = {38672954},
issn = {2304-8158},
abstract = {γ-aminobutyric acid (GABA), recognized as a primary inhibitory neurotransmitter within the brain, serves a crucial role in the aging process and in neurodegenerative conditions such as Alzheimer's disease. Research has demonstrated the beneficial effects of GABA, particularly for elderly individuals. Given that elderly individuals often encounter challenges with swallowing food, beverages designed to address dysphagia represent a preferable option for this demographic. Among the different processing techniques, the germination process triggers biochemical changes, leading to an increase in certain nutrients and bioactive compounds (e.g., GABA). Therefore, we attempted to develop a novel functional beverage utilizing germinated brown rice enriched with GABA and studied its nutritional and bio-functional characterization. The optimal conditions (X1, X2, X3 and X4.) were determined: powdered sugar (40 g), chocolate powder (20 g), sodium carboxymethyl cellulose (0.5 g), GBR (220 g), and water (440 mL). The results of storage studies indicated that the germinated-brown-rice-based beverage exhibited favorable nutritional attributes, including increased γ-oryzanol (52.73 ± 1.56%), total phenolic content (26.68 ± 1.56 mg GAE/100 g), niacin (5.17 ± 0.14%), and GABA (42.12 ± 0.63 mg/100 g) levels. Additionally, the beverage demonstrated notable antioxidant activity (74.23 ± 2.37 µmol TE/100 g), suggesting potential health-promoting effects. Sensory evaluation revealed satisfactory acceptability among consumers, highlighting its palatability. Overall, this study elucidates the development of a novel functional beverage utilizing germinated brown rice enriched with GABA, offering promising nutritional and bio-functional characteristics for health-conscious consumers.},
}

@article {pmid38672806,
year = {2024},
author = {Tallini, LR and Manfredini, G and Rodríguez-Escobar, ML and Ríos, S and Martínez-Francés, V and Feresin, GE and Borges, WS and Bastida, J and Viladomat, F and Torras-Claveria, L},
title = {The Anti-Cholinesterase Potential of Fifteen Different Species of Narcissus L. (Amaryllidaceae) Collected in Spain.},
journal = {Life (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/life14040536},
pmid = {38672806},
issn = {2075-1729},
support = {223RT0140//Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo/ ; },
abstract = {Narcissus L. is a renowned plant genus with a notable center of diversity and is primarily located in the Mediterranean region. These plants are widely recognized for their ornamental value, owing to the beauty of their flowers; nonetheless, they also hold pharmacological importance. In Europe, pharmaceutical companies usually use the bulbs of Narcissus pseudonarcissus cv. Carlton to extract galanthamine, which is one of the few medications approved by the FDA for the palliative treatment of mild-to-moderate symptoms of Alzheimer's disease. The purpose of this study was to evaluate the potential of these plants in Alzheimer's disease. The alkaloid extract from the leaves of different species of Narcissus was obtained by an acid-base extraction work-up -procedure. The biological potential of the samples was carried out by evaluating their ability to inhibit the enzymes acetyl- and butyrylcholinesterase (AChE and BuChE, respectively). The species N. jacetanus exhibited the best inhibition values against AChE, with IC50 values of 0.75 ± 0.03 µg·mL[-1], while N. jonquilla was the most active against BuChE, with IC50 values of 11.72 ± 1.15 µg·mL[-1].},
}

@article {pmid38672774,
year = {2024},
author = {Wani, I and Koppula, S and Balda, A and Thekkekkara, D and Jamadagni, A and Walse, P and Manjula, SN and Kopalli, SR},
title = {An Update on the Potential of Tangeretin in the Management of Neuroinflammation-Mediated Neurodegenerative Disorders.},
journal = {Life (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/life14040504},
pmid = {38672774},
issn = {2075-1729},
abstract = {Neuroinflammation is the major cause of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Currently available drugs present relatively low efficacy and are not capable of modifying the course of the disease or delaying its progression. Identifying well-tolerated and brain-penetrant agents of plant origin could fulfil the pressing need for novel treatment techniques for neuroinflammation. Attention has been drawn to a large family of flavonoids in citrus fruits, which may function as strong nutraceuticals in slowing down the development and progression of neuroinflammation. This review is aimed at elucidating and summarizing the effects of the flavonoid tangeretin (TAN) in the management of neuroinflammation-mediated neurodegenerative disorders. A literature survey was performed using various resources, including ScienceDirect, PubMed, Google Scholar, Springer, and Web of Science. The data revealed that TAN exhibited immense neuroprotective effects in addition to its anti-oxidant, anti-diabetic, and peroxisome proliferator-activated receptor-γ agonistic effects. The effects of TAN are mainly mediated through the inhibition of oxidative and inflammatory pathways via regulating multiple signaling pathways, including c-Jun N-terminal kinase, phosphoinositide 3-kinase, mitogen-activated protein kinase, nuclear factor erythroid-2-related factor 2, extracellular-signal-regulated kinase, and CRE-dependent transcription. In conclusion, the citrus flavonoid TAN has the potential to prevent neuronal death mediated by neuroinflammatory pathways and can be developed as an auxiliary therapeutic agent in the management of neurodegenerative disorders.},
}

@article {pmid38672471,
year = {2024},
author = {Varrias, D and Saralidze, T and Borkowski, P and Pargaonkar, S and Spanos, M and Bazoukis, G and Kokkinidis, D},
title = {Atrial Fibrillation and Dementia: Pathophysiological Mechanisms and Clinical Implications.},
journal = {Biomolecules},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biom14040455},
pmid = {38672471},
issn = {2218-273X},
mesh = {*Atrial Fibrillation/physiopathology/complications ; Humans ; *Dementia/etiology/physiopathology ; Risk Factors ; Cognitive Dysfunction/physiopathology/etiology ; Stroke/physiopathology/complications ; },
abstract = {Numerous longitudinal studies suggest a strong association between cardiovascular risk factors and cognitive impairment. Individuals with atrial fibrillation are at higher risk of dementia and cognitive dysfunction, as atrial fibrillation increases the risk of cerebral hypoperfusion, inflammation, and stroke. The lack of comprehensive understanding of the observed association and the complex relationship between these two diseases makes it very hard to provide robust guidelines on therapeutic indications. With this review, we attempt to shed some light on how atrial fibrillation is related to dementia, what we know regarding preventive interventions, and how we could move forward in managing those very frequently overlapping conditions.},
}

*Atrial Fibrillation/physiopathology/complications
Humans
*Dementia/etiology/physiopathology
Risk Factors
Cognitive Dysfunction/physiopathology/etiology
Stroke/physiopathology/complications

@article {pmid38672443,
year = {2024},
author = {Lymperopoulos, D and Dedemadi, AG and Voulgari, ML and Georgiou, E and Dafnis, I and Mountaki, C and Panagopoulou, EA and Karvelas, M and Chiou, A and Karathanos, VT and Chroni, A},
title = {Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer's Disease.},
journal = {Biomolecules},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biom14040426},
pmid = {38672443},
issn = {2218-273X},
support = {T1EDK-04290, MIS 5030607//Operational Program Competitiveness, Entrepreneurship and Innovation of Greece/ ; },
abstract = {Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer's disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian currant paste-supplemented diet (CurD), provided to 1-month-old 5xFAD mice for 1, 3, and 6 months, on PON1 activity and levels of oxidation markers in serum and the brain of mice as compared to a control diet (ConD) or glucose/fructose-matched diet (GFD). Administration of CurD for 1 month increased PON1 activity and decreased oxidized lipid levels in serum compared to ConD and GFD. Longer-term administration of CurD did not, however, affect serum PON1 activity and oxidized lipid levels. Furthermore, CurD administered for 1 and 3 months, but not for 6 months, increased PON1 activity and decreased free radical levels in the cortex of mice compared to ConD and GFD. To probe the mechanism for the increased PON1 activity in mice, we studied the effect of Corinthian currant polar phenolic extract on PON1 activity secreted by Huh-7 hepatocytes or HEK293 cells transfected with a PON1-expressing plasmid. Incubation of cells with the extract led to a dose-dependent increase of secreted PON1 activity, which was attributed to increased cellular PON1 expression. Collectively, our findings suggest that phenolics in Corinthian currants can increase the hepatic expression and activity of antioxidant enzyme PON1 and that a Corinthian currant-supplemented diet during the early stages of AD in mice reduces brain oxidative stress.},
}

@article {pmid38672426,
year = {2024},
author = {Xiao, H and Zou, Y and Wang, J and Wan, S},
title = {A Review for Artificial Intelligence Based Protein Subcellular Localization.},
journal = {Biomolecules},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biom14040409},
pmid = {38672426},
issn = {2218-273X},
support = {P30CA036727/NH/NIH HHS/United States ; CA036727/CA/NCI NIH HHS/United States ; P50AA030407-5126/AA/NIAAA NIH HHS/United States ; },
mesh = {*Artificial Intelligence ; Humans ; Proteins/metabolism/chemistry/analysis ; Machine Learning ; Proteomics/methods ; Animals ; Deep Learning ; },
abstract = {Proteins need to be located in appropriate spatiotemporal contexts to carry out their diverse biological functions. Mislocalized proteins may lead to a broad range of diseases, such as cancer and Alzheimer's disease. Knowing where a target protein resides within a cell will give insights into tailored drug design for a disease. As the gold validation standard, the conventional wet lab uses fluorescent microscopy imaging, immunoelectron microscopy, and fluorescent biomarker tags for protein subcellular location identification. However, the booming era of proteomics and high-throughput sequencing generates tons of newly discovered proteins, making protein subcellular localization by wet-lab experiments a mission impossible. To tackle this concern, in the past decades, artificial intelligence (AI) and machine learning (ML), especially deep learning methods, have made significant progress in this research area. In this article, we review the latest advances in AI-based method development in three typical types of approaches, including sequence-based, knowledge-based, and image-based methods. We also elaborately discuss existing challenges and future directions in AI-based method development in this research field.},
}

*Artificial Intelligence
Humans
Proteins/metabolism/chemistry/analysis
Machine Learning
Proteomics/methods
Animals
Deep Learning

@article {pmid38672416,
year = {2024},
author = {Cheslow, L and Snook, AE and Waldman, SA},
title = {Biomarkers for Managing Neurodegenerative Diseases.},
journal = {Biomolecules},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biom14040398},
pmid = {38672416},
issn = {2218-273X},
support = {1R01 CA204881, 1R01 CA206026, 1R21 1NS130388, 1R01 DK1388341/NH/NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/metabolism/diagnosis/therapy ; *Alzheimer Disease/metabolism/diagnosis/therapy ; Amyotrophic Lateral Sclerosis/metabolism/therapy/diagnosis ; Parkinson Disease/metabolism/diagnosis/therapy ; Animals ; },
abstract = {Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).},
}

Humans
*Biomarkers/metabolism
*Neurodegenerative Diseases/metabolism/diagnosis/therapy
*Alzheimer Disease/metabolism/diagnosis/therapy
Amyotrophic Lateral Sclerosis/metabolism/therapy/diagnosis
Parkinson Disease/metabolism/diagnosis/therapy
Animals

@article {pmid38672412,
year = {2024},
author = {Lachén-Montes, M and Cartas-Cejudo, P and Cortés, A and Anaya-Cubero, E and Peral, E and Ausín, K and Díaz-Peña, R and Fernández-Irigoyen, J and Santamaría, E},
title = {Involvement of Glucosamine 6 Phosphate Isomerase 2 (GNPDA2) Overproduction in β-Amyloid- and Tau P301L-Driven Pathomechanisms.},
journal = {Biomolecules},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/biom14040394},
pmid = {38672412},
issn = {2218-273X},
support = {0011-1411-2020-000028 and 0011-1411-2023-000028//Gobierno de Navarra/ ; PID2019-110356RB-I00/AEI/10.13039/501100011033//Spanish Ministry of Science, Innovation and Universities/ ; },
mesh = {Humans ; Animals ; *Zebrafish/metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; Animals, Genetically Modified ; Aldose-Ketose Isomerases/metabolism/genetics ; Cell Proliferation ; Epithelial Cells/metabolism ; Proteomics ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative olfactory disorder affecting millions of people worldwide. Alterations in the hexosamine- or glucose-related pathways have been described through AD progression. Specifically, an alteration in glucosamine 6 phosphate isomerase 2 (GNPDA2) protein levels has been observed in olfactory areas of AD subjects. However, the biological role of GNPDA2 in neurodegeneration remains unknown. Using mass spectrometry, multiple GNPDA2 interactors were identified in human nasal epithelial cells (NECs) mainly involved in intraciliary transport. Moreover, GNPDA2 overexpression induced an increment in NEC proliferation rates, accompanied by transcriptomic alterations in Type II interferon signaling or cellular stress responses. In contrast, the presence of beta-amyloid or mutated Tau-P301L in GNPDA2-overexpressing NECs induced a slowdown in the proliferative capacity in parallel with a disruption in protein processing. The proteomic characterization of Tau-P301L transgenic zebrafish embryos demonstrated that GNPDA2 overexpression interfered with collagen biosynthesis and RNA/protein processing, without inducing additional changes in axonal outgrowth defects or neuronal cell death. In humans, a significant increase in serum GNPDA2 levels was observed across multiple neurological proteinopathies (AD, Lewy body dementia, progressive supranuclear palsy, mixed dementia and amyotrophic lateral sclerosis) (n = 215). These data shed new light on GNPDA2-dependent mechanisms associated with the neurodegenerative process beyond the hexosamine route.},
}

Humans
Animals
*Zebrafish/metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism/genetics
*Alzheimer Disease/metabolism/genetics/pathology
Animals, Genetically Modified
Aldose-Ketose Isomerases/metabolism/genetics
Cell Proliferation
Epithelial Cells/metabolism
Proteomics

@article {pmid38672280,
year = {2024},
author = {Altay, O and Yang, H and Yildirim, S and Bayram, C and Bolat, I and Oner, S and Tozlu, OO and Arslan, ME and Hacimuftuoglu, A and Shoaie, S and Zhang, C and Borén, J and Uhlén, M and Turkez, H and Mardinoglu, A},
title = {Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases.},
journal = {Biomedicines},
volume = {12},
number = {4},
pages = {},
doi = {10.3390/biomedicines12040927},
pmid = {38672280},
issn = {2227-9059},
support = {72110//Knut and Alice Wallenberg Foundation/ ; },
abstract = {BACKGROUND: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate.

METHODS: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations.

FINDINGS: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals.

INTERPRETATION: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.},
}

@article {pmid38672253,
year = {2024},
author = {Cheung, EYW and Wu, RWK and Chu, ESM and Mak, HKF},
title = {Integrating Demographics and Imaging Features for Various Stages of Dementia Classification: Feed Forward Neural Network Multi-Class Approach.},
journal = {Biomedicines},
volume = {12},
number = {4},
pages = {},
doi = {10.3390/biomedicines12040896},
pmid = {38672253},
issn = {2227-9059},
support = {220209/WT_/Wellcome Trust/United Kingdom ; },
abstract = {BACKGROUND: MRI magnetization-prepared rapid acquisition (MPRAGE) is an easily available imaging modality for dementia diagnosis. Previous studies suggested that volumetric analysis plays a crucial role in various stages of dementia classification. In this study, volumetry, radiomics and demographics were integrated as inputs to develop an artificial intelligence model for various stages, including Alzheimer's disease (AD), mild cognitive decline (MCI) and cognitive normal (CN) dementia classifications.

METHOD: The Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset was separated into training and testing groups, and the Open Access Series of Imaging Studies (OASIS) dataset was used as the second testing group. The MRI MPRAGE image was reoriented via statistical parametric mapping (SPM12). Freesurfer was employed for brain segmentation, and 45 regional brain volumes were retrieved. The 3D Slicer software was employed for 107 radiomics feature extractions from within the whole brain. Data on patient demographics were collected from the datasets. The feed-forward neural network (FFNN) and the other most common artificial intelligence algorithms, including support vector machine (SVM), ensemble classifier (EC) and decision tree (DT), were used to build the models using various features.

RESULTS: The integration of brain regional volumes, radiomics and patient demographics attained the highest overall accuracy at 76.57% and 73.14% in ADNI and OASIS testing, respectively. The subclass accuracies in MCI, AD and CN were 78.29%, 89.71% and 85.14%, respectively, in ADNI testing, as well as 74.86%, 88% and 83.43% in OASIS testing. Balanced sensitivity and specificity were obtained for all subclass classifications in MCI, AD and CN.

CONCLUSION: The FFNN yielded good overall accuracy for MCI, AD and CN categorization, with balanced subclass accuracy, sensitivity and specificity. The proposed FFNN model is simple, and it may support the triage of patients for further confirmation of the diagnosis.},
}

@article {pmid38672142,
year = {2024},
author = {Jarek, DJ and Mizerka, H and Nuszkiewicz, J and Szewczyk-Golec, K},
title = {Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer's Disease: A Narrative Review.},
journal = {Biomedicines},
volume = {12},
number = {4},
pages = {},
doi = {10.3390/biomedicines12040786},
pmid = {38672142},
issn = {2227-9059},
abstract = {The escalating prevalence of Alzheimer's disease (AD) highlights the urgent need to develop reliable biomarkers for early diagnosis and intervention. AD is characterized by the pathological accumulation of amyloid-beta plaques and tau neurofibrillary tangles. Phosphorylated tau (p-tau) proteins, particularly p-tau217 and p-tau231, have been identified as promising biomarker candidates to differentiate the disease progression from preclinical stages. This narrative review is devoted to a critical evaluation of the diagnostic accuracy, sensitivity, and specificity of p-tau217 and p-tau231 levels in the detection of AD, measured in plasma, serum, and cerebrospinal fluid, compared to established biomarkers. Additionally, the efficacy of these markers in distinguishing AD from other neurodegenerative disorders is examined. The significant advances offered by p-tau217 and p-tau231 in AD diagnostics are highlighted, demonstrating their unique utility in early detection and differential diagnosis. This comprehensive analysis not only confirms the excellent diagnostic capabilities of these markers, but also deepens the understanding of the molecular dynamics of AD, contributing to the broader scientific discourse on neurodegenerative diseases. This review is aimed to provide key information for researchers and clinicians across disciplines, filling interdisciplinary gaps and highlighting the role of p-tau proteins in revolutionizing AD research and clinical practice.},
}

@article {pmid38672055,
year = {2024},
author = {Yamao, T and Miwa, K and Kaneko, Y and Takahashi, N and Miyaji, N and Hasegawa, K and Wagatsuma, K and Kamitaka, Y and Ito, H and Matsuda, H},
title = {Deep Learning-Driven Estimation of Centiloid Scales from Amyloid PET Images with [11]C-PiB and [18]F-Labeled Tracers in Alzheimer's Disease.},
journal = {Brain sciences},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/brainsci14040406},
pmid = {38672055},
issn = {2076-3425},
abstract = {BACKGROUND: Standard methods for deriving Centiloid scales from amyloid PET images are time-consuming and require considerable expert knowledge. We aimed to develop a deep learning method of automating Centiloid scale calculations from amyloid PET images with [11]C-Pittsburgh Compound-B (PiB) tracer and assess its applicability to [18]F-labeled tracers without retraining.

METHODS: We trained models on 231 [11]C-PiB amyloid PET images using a 50-layer 3D ResNet architecture. The models predicted the Centiloid scale, and accuracy was assessed using mean absolute error (MAE), linear regression analysis, and Bland-Altman plots.

RESULTS: The MAEs for Alzheimer's disease (AD) and young controls (YC) were 8.54 and 2.61, respectively, using [11]C-PiB, and 8.66 and 3.56, respectively, using [18]F-NAV4694. The MAEs for AD and YC were higher with [18]F-florbetaben (39.8 and 7.13, respectively) and [18]F-florbetapir (40.5 and 12.4, respectively), and the error rate was moderate for [18]F-flutemetamol (21.3 and 4.03, respectively). Linear regression yielded a slope of 1.00, intercept of 1.26, and R[2] of 0.956, with a mean bias of -1.31 in the Centiloid scale prediction.

CONCLUSIONS: We propose a deep learning means of directly predicting the Centiloid scale from amyloid PET images in a native space. Transferring the model trained on [11]C-PiB directly to [18]F-NAV4694 without retraining was feasible.},
}

@article {pmid38671987,
year = {2024},
author = {Lal, U and Chikkankod, AV and Longo, L},
title = {A Comparative Study on Feature Extraction Techniques for the Discrimination of Frontotemporal Dementia and Alzheimer's Disease with Electroencephalography in Resting-State Adults.},
journal = {Brain sciences},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/brainsci14040335},
pmid = {38671987},
issn = {2076-3425},
abstract = {Early-stage Alzheimer's disease (AD) and frontotemporal dementia (FTD) share similar symptoms, complicating their diagnosis and the development of specific treatment strategies. Our study evaluated multiple feature extraction techniques for identifying AD and FTD biomarkers from electroencephalographic (EEG) signals. We developed an optimised machine learning architecture that integrates sliding windowing, feature extraction, and supervised learning to distinguish between AD and FTD patients, as well as from healthy controls (HCs). Our model, with a 90% overlap for sliding windowing, SVD entropy for feature extraction, and K-Nearest Neighbors (KNN) for supervised learning, achieved a mean F1-score and accuracy of 93% and 91%, 92.5% and 93%, and 91.5% and 91% for discriminating AD and HC, FTD and HC, and AD and FTD, respectively. The feature importance array, an explainable AI feature, highlighted the brain lobes that contributed to identifying and distinguishing AD and FTD biomarkers. This research introduces a novel framework for detecting and discriminating AD and FTD using EEG signals, addressing the need for accurate early-stage diagnostics. Furthermore, a comparative evaluation of sliding windowing, multiple feature extraction, and machine learning methods on AD/FTD detection and discrimination is documented.},
}

@article {pmid38671980,
year = {2024},
author = {Greuel, BK and Da Silva, DE and Robert-Gostlin, VN and Klegeris, A},
title = {Natural Compounds Oridonin and Shikonin Exhibit Potentially Beneficial Regulatory Effects on Select Functions of Microglia.},
journal = {Brain sciences},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/brainsci14040328},
pmid = {38671980},
issn = {2076-3425},
support = {not applicable//Natural Sciences and Engineering Research Council/ ; not applicable//Jack Brown and Family Alzheimer Research Foundation/ ; },
abstract = {Accumulating evidence indicates that the adverse neuroimmune activation of microglia, brain immunocytes that support neurons, contributes to a range of neuroinflammatory disorders, including Alzheimer's disease. Correcting the abnormal functions of microglia is a potential therapeutic strategy for these diseases. Nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor (NLRP) 3 inflammasomes are implicated in adverse microglial activation and their inhibitors, such as the natural compounds oridonin and shikonin, reduce microglial immune responses. We hypothesized that some of the beneficial effects of oridonin and shikonin on microglia are independent of their suppression of NLRP3 inflammasomes. Murine and human microglia-like cells were stimulated with bacterial lipopolysaccharide (LPS) only, which did not induce NLRP3 inflammasome activation or the resulting secretion of interleukin (IL)-1β, allowing for the identification of other anti-inflammatory effects. Under these experimental conditions, both oridonin and shikonin reduced nitric oxide (NO) secretion and the cytotoxicity of BV-2 murine microglia towards HT-22 murine neuronal cells, but upregulated BV-2 cell phagocytic activity. Only oridonin inhibited the secretion of tumor necrosis factor (TNF) by stimulated BV-2 microglia, while only shikonin suppressed the respiratory burst response of human HL-60 microglia-like cells. This observed discrepancy indicates that these natural compounds may have different molecular targets in microglia. Overall, our results suggest that oridonin and shikonin should be further investigated as pharmacological agents capable of correcting dysfunctional microglia, supporting their potential use in neuroinflammatory disorders.},
}

@article {pmid38671950,
year = {2024},
author = {Branigan, KS and Dotta, BT},
title = {Cognitive Decline: Current Intervention Strategies and Integrative Therapeutic Approaches for Alzheimer's Disease.},
journal = {Brain sciences},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/brainsci14040298},
pmid = {38671950},
issn = {2076-3425},
abstract = {Alzheimer's disease (AD) represents a pressing global health challenge, with an anticipated surge in diagnoses over the next two decades. This progressive neurodegenerative disorder unfolds gradually, with observable symptoms emerging after two decades of imperceptible brain changes. While traditional therapeutic approaches, such as medication and cognitive therapy, remain standard in AD management, their limitations prompt exploration into novel integrative therapeutic approaches. Recent advancements in AD research focus on entraining gamma waves through innovative methods, such as light flickering and electromagnetic fields (EMF) stimulation. Flickering light stimulation (FLS) at 40 Hz has demonstrated significant reductions in AD pathologies in both mice and humans, providing improved cognitive functioning. Additionally, recent experiments have demonstrated that APOE mutations in mouse models substantially reduce tau pathologies, with microglial modulation playing a crucial role. EMFs have also been demonstrated to modulate microglia. The exploration of EMFs as a therapeutic approach is gaining significance, as many recent studies have showcased their potential to influence microglial responses. Th article concludes by speculating on the future directions of AD research, emphasizing the importance of ongoing efforts in understanding the complexities of AD pathogenesis through a holistic approach and developing interventions that hold promise for improved patient outcomes.},
}

@article {pmid38671931,
year = {2024},
author = {Scuto, M and Rampulla, F and Reali, GM and Spanò, SM and Trovato Salinaro, A and Calabrese, V},
title = {Hormetic Nutrition and Redox Regulation in Gut-Brain Axis Disorders.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
doi = {10.3390/antiox13040484},
pmid = {38671931},
issn = {2076-3921},
abstract = {The antioxidant and anti-inflammatory effects of hormetic nutrition for enhancing stress resilience and overall human health have received much attention. Recently, the gut-brain axis has attracted prominent interest for preventing and therapeutically impacting neuropathologies and gastrointestinal diseases. Polyphenols and polyphenol-combined nanoparticles in synergy with probiotics have shown to improve gut bioavailability and blood-brain barrier (BBB) permeability, thus inhibiting the oxidative stress, metabolic dysfunction and inflammation linked to gut dysbiosis and ultimately the onset and progression of central nervous system (CNS) disorders. In accordance with hormesis, polyphenols display biphasic dose-response effects by activating at a low dose the Nrf2 pathway resulting in the upregulation of antioxidant vitagenes, as in the case of heme oxygenase-1 upregulated by hidrox[®] or curcumin and sirtuin-1 activated by resveratrol to inhibit reactive oxygen species (ROS) overproduction, microbiota dysfunction and neurotoxic damage. Importantly, modulation of the composition and function of the gut microbiota through polyphenols and/or probiotics enhances the abundance of beneficial bacteria and can prevent and treat Alzheimer's disease and other neurological disorders. Interestingly, dysregulation of the Nrf2 pathway in the gut and the brain can exacerbate selective susceptibility under neuroinflammatory conditions to CNS disorders due to the high vulnerability of vagal sensory neurons to oxidative stress. Herein, we aimed to discuss hormetic nutrients, including polyphenols and/or probiotics, targeting the Nrf2 pathway and vitagenes for the development of promising neuroprotective and therapeutic strategies to suppress oxidative stress, inflammation and microbiota deregulation, and consequently improve cognitive performance and brain health. In this review, we also explore interactions of the gut-brain axis based on sophisticated and cutting-edge technologies for novel anti-neuroinflammatory approaches and personalized nutritional therapies.},
}

@article {pmid38671908,
year = {2024},
author = {Goujon, M and Liang, Z and Soriano-Castell, D and Currais, A and Maher, P},
title = {The Neuroprotective Flavonoids Sterubin and Fisetin Maintain Mitochondrial Health under Oxytotic/Ferroptotic Stress and Improve Bioenergetic Efficiency in HT22 Neuronal Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
doi = {10.3390/antiox13040460},
pmid = {38671908},
issn = {2076-3921},
abstract = {The global increase in the aging population has led to a rise in many age-related diseases with continuing unmet therapeutic needs. Research into the molecular mechanisms underlying both aging and neurodegeneration has identified promising therapeutic targets, such as the oxytosis/ferroptosis cell death pathway, in which mitochondrial dysfunction plays a critical role. This study focused on sterubin and fisetin, two flavonoids from the natural pharmacopeia previously identified as strong inhibitors of the oxytosis/ferroptosis pathway. Here, we investigated the effects of the compounds on the mitochondrial physiology in HT22 hippocampal nerve cells under oxytotic/ferroptotic stress. We show that the compounds can restore mitochondrial homeostasis at the level of redox regulation, calcium uptake, biogenesis, fusion/fission dynamics, and modulation of respiration, leading to the enhancement of bioenergetic efficiency. However, mitochondria are not required for the neuroprotective effects of sterubin and fisetin, highlighting their diverse homeostatic impacts. Sterubin and fisetin, thus, provide opportunities to expand drug development strategies for anti-oxytotic/ferroptotic agents and offer new perspectives on the intricate interplay between mitochondrial function, cellular stress, and the pathophysiology of aging and age-related neurodegenerative disorders.},
}

@article {pmid38671883,
year = {2024},
author = {Staurenghi, E and Testa, G and Leoni, V and Cecci, R and Floro, L and Giannelli, S and Barone, E and Perluigi, M and Leonarduzzi, G and Sottero, B and Gamba, P},
title = {Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
doi = {10.3390/antiox13040435},
pmid = {38671883},
issn = {2076-3921},
support = {LEOG_RILO_22_01//University of Turin/ ; GAMP_RILO_22_01//University of Turin/ ; 2019-ATE-0481//University of Milano-Bicocca/ ; },
abstract = {Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer's disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol imbalances also likely occur in DS, concurring with the precocious AD-like neurodegeneration. In this pilot study, we analyzed, in the brain of the Ts2Cje (Ts2) mouse model of DS, the expression of genes encoding key enzymes involved in cholesterol metabolism and of the levels of cholesterol and its main precursors and products of its metabolism (i.e., oxysterols). The results showed, in Ts2 mice compared to euploid mice, the downregulation of the transcription of the genes encoding the enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and 24-dehydrocholesterol reductase, the latter originally recognized as an indicator of AD, and the consequent reduction in total cholesterol levels. Moreover, the expression of genes encoding enzymes responsible for brain cholesterol oxidation and the amounts of the resulting oxysterols were modified in Ts2 mouse brains, and the levels of cholesterol autoxidation products were increased, suggesting an exacerbation of cerebral oxidative stress. We also observed an enhanced inflammatory response in Ts2 mice, underlined by the upregulation of the transcription of the genes encoding for α-interferon and interleukin-6, two cytokines whose synthesis is increased in the brains of AD patients. Overall, these results suggest that DS and AD brains share cholesterol cycle derangements and altered oxysterol levels, which may contribute to the oxidative and inflammatory events involved in both diseases.},
}

@article {pmid38671841,
year = {2024},
author = {Valotto Neto, LJ and Reverete de Araujo, M and Moretti Junior, RC and Mendes Machado, N and Joshi, RK and Dos Santos Buglio, D and Barbalho Lamas, C and Direito, R and Fornari Laurindo, L and Tanaka, M and Barbalho, SM},
title = {Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
doi = {10.3390/antiox13040393},
pmid = {38671841},
issn = {2076-3921},
abstract = {The aging of the global population has increased the prevalence of neurodegenerative conditions. Bacopa monnieri (BM), an herb with active compounds, such as bacosides A and B, betulinic acid, loliolide, asiatic acid, and quercetin, demonstrates the potential for brain health. Limited research has been conducted on the therapeutic applications of BM in neurodegenerative conditions. This systematic review aims to project BM's beneficial role in brain disorders. BM has anti-apoptotic and antioxidant actions and can repair damaged neurons, stimulate kinase activity, restore synaptic function, improve nerve transmission, and increase neuroprotection. The included twenty-two clinical trials demonstrated that BM can reduce Nuclear Factor-κB phosphorylation, improve emotional function, cognitive functions, anhedonia, hyperactivity, sleep routine, depression, attention deficit, learning problems, memory retention, impulsivity, and psychiatric problems. Moreover, BM can reduce the levels of pro-inflammatory biomarkers and oxidative stress. Here, we highlight that BM provides notable therapeutic benefits and can serve as a complementary approach for the care of patients with neurodegenerative conditions associated with brain disorders. This review adds to the growing interest in natural products and their potential therapeutic applications by improving our understanding of the mechanisms underlying cognitive function and neurodegeneration and informing the development of new therapeutic strategies for neurodegenerative diseases.},
}

@article {pmid38671746,
year = {2024},
author = {Cataldo, A and Criscuolo, S and De Benedetto, E and Masciullo, A and Pesola, M and Schiavoni, R},
title = {A Novel Metric for Alzheimer's Disease Detection Based on Brain Complexity Analysis via Multiscale Fuzzy Entropy.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {11},
number = {4},
pages = {},
doi = {10.3390/bioengineering11040324},
pmid = {38671746},
issn = {2306-5354},
abstract = {Alzheimer's disease (AD) is a neurodegenerative brain disorder that affects cognitive functioning and memory. Current diagnostic tools, including neuroimaging techniques and cognitive questionnaires, present limitations such as invasiveness, high costs, and subjectivity. In recent years, interest has grown in using electroencephalography (EEG) for AD detection due to its non-invasiveness, low cost, and high temporal resolution. In this regard, this work introduces a novel metric for AD detection by using multiscale fuzzy entropy (MFE) to assess brain complexity, offering clinicians an objective, cost-effective diagnostic tool to aid early intervention and patient care. To this purpose, brain entropy patterns in different frequency bands for 35 healthy subjects (HS) and 35 AD patients were investigated. Then, based on the resulting MFE values, a specific detection algorithm, able to assess brain complexity abnormalities that are typical of AD, was developed and further validated on 24 EEG test recordings. This MFE-based method achieved an accuracy of 83% in differentiating between HS and AD, with a diagnostic odds ratio of 25, and a Matthews correlation coefficient of 0.67, indicating its viability for AD diagnosis. Furthermore, the algorithm showed potential for identifying anomalies in brain complexity when tested on a subject with mild cognitive impairment (MCI), warranting further investigation in future research.},
}

@article {pmid38671545,
year = {2024},
author = {Holland, N and Savulich, G and Jones, PS and Whiteside, DJ and Street, D and Swann, P and Naessens, M and Malpetti, M and Hong, YT and Fryer, TD and Rittman, T and Mulroy, E and Aigbirhio, FI and Bhatia, KP and O'Brien, JT and Rowe, JB},
title = {Differential Synaptic Loss in β-Amyloid Positive Versus β-Amyloid Negative Corticobasal Syndrome.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.29814},
pmid = {38671545},
issn = {1531-8257},
support = {220258/WT_/Wellcome Trust/United Kingdom ; MC_UU_00030/14/MRC_/Medical Research Council/United Kingdom ; MR/T033371/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to β-amyloid status.

METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [[11]C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [[18]F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had β-amyloid imaging with [11]C-labeled Pittsburgh Compound-B ([[11]C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA.

RESULTS: Compared to controls, patients with CBS had higher [[18]F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the β-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side.

DISCUSSION: Distinct patterns of [[11]C]UCB-J and [[18]F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid38671492,
year = {2024},
author = {Jiang, D and Liu, H and Li, T and Zhao, S and Yang, K and Yao, F and Zhou, B and Feng, H and Wang, S and Shen, J and Tang, J and Zhang, YX and Wang, Y and Guo, C and Tang, TS},
title = {Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {13},
number = {1},
pages = {24},
pmid = {38671492},
issn = {2047-9158},
support = {82030033//National Natural Science Foundation of China/ ; 81921006//National Natural Science Foundation of China/ ; 92254301//National Natural Science Foundation of China/ ; 82341006//National Natural Science Foundation of China/ ; 32070780//National Natural Science Foundation of China/ ; 82330090//National Natural Science Foundation of China/ ; IS23071//Beijing Natural Science Foundation/ ; },
mesh = {Animals ; *Neurogenesis/drug effects/physiology ; *Alzheimer Disease/genetics ; *Hippocampus/drug effects/metabolism ; *Carboxypeptidase H/genetics/biosynthesis ; *Up-Regulation ; Mice ; *Memory Disorders/genetics/etiology ; Brain-Derived Neurotrophic Factor/biosynthesis/genetics/metabolism ; MicroRNAs/genetics/biosynthesis ; Male ; Mice, Transgenic ; Mice, Inbred C57BL ; Disease Models, Animal ; },
abstract = {BACKGROUND: Adult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer's disease (AD).

METHODS: In vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation.

RESULTS: Restoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5'UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice.

CONCLUSIONS: CPE may regulate adult hippocampal neurogenesis via the CPE-BDNF-TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.},
}

Animals
*Neurogenesis/drug effects/physiology
*Alzheimer Disease/genetics
*Hippocampus/drug effects/metabolism
*Carboxypeptidase H/genetics/biosynthesis
*Up-Regulation
Mice
*Memory Disorders/genetics/etiology
Brain-Derived Neurotrophic Factor/biosynthesis/genetics/metabolism
MicroRNAs/genetics/biosynthesis
Male
Mice, Transgenic
Mice, Inbred C57BL
Disease Models, Animal

@article {pmid38671330,
year = {2024},
author = {Kam, MK and Park, JY and Yun, GH and Sohn, HY and Park, JH and Choi, J and Koh, YH and Jo, C},
title = {Rottlerin Enhances the Autophagic Degradation of Phosphorylated Tau in Neuronal Cells.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {38671330},
issn = {1559-1182},
support = {2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; 2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; 2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; 2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; 2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; 2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; 2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; 2022-NG-008-01//Korea Disease Control and Prevention Agency/ ; },
abstract = {Intra-neuronal accumulation of hyper-phosphorylated tau as neurofibrillary tangles (NFT) is a hallmark of Alzheimer's disease (AD). To prevent the aggregation of phosphorylated tau in neurons, decreasing the phosphorylated tau protein levels is important. Here, we examined the biological effects of rottlerin, a phytochemical compound extracted from the Kamala tree, Mallotus philippinensis, on phosphorylated tau levels. Notably, rottlerin decreased the levels of intracellular phosphorylated and total tau. A marked increase in the LC3-II, a hallmark of autophagy, was observed in these cells, indicating that rottlerin strongly induced autophagy. Interestingly, rottlerin induced the phosphorylation of Raptor at S792 through the activation of adenosine-monophosphate activated-protein kinase (AMPK), which likely inhibits the mammalian target of rapamycin complex 1 (mTORC1), thus resulting in the activation of transcription factor EB (TFEB), a master regulator of autophagy. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) activity increased in the presence of rottlerin. The decrease of phosphorylated tau levels in the presence of rottlerin was ameliorated by the knockdown of TFEB and partially attenuated by the knockout of the Nrf2 gene. Taken together, rottlerin likely enhances the degradation of phosphorylated tau through autophagy activated by TFEB and Nrf2. Thus, our results suggest that a natural compound rottlerin could be used as a preventive and therapeutic drug for AD.},
}

@article {pmid38671226,
year = {2024},
author = {Wang, J and He, Y and Liu, L and Chen, X and Hou, X and Wang, J and Yi, X},
title = {DNA tetrahedron-based dual-signal fluorescence detection of apoE4 gene sites on a microplate reader.},
journal = {Mikrochimica acta},
volume = {191},
number = {5},
pages = {288},
pmid = {38671226},
issn = {1436-5073},
support = {22076221//National Natural Science Foundation of China/ ; 21876208//National Natural Science Foundation of China/ ; 22105011//National Natural Science Foundation of China/ ; 2023CXQD022//Innovation-Driven Project of Central South University/ ; 2019TP1001//Hunan Provincial Science and Technology Plan Project/ ; },
mesh = {*Apolipoprotein E4/genetics ; *Fluorescence Resonance Energy Transfer/methods ; Humans ; *Fluorescent Dyes/chemistry ; *DNA/chemistry/genetics ; *Carbocyanines/chemistry ; Benzothiazoles/chemistry ; Nanostructures/chemistry ; Quinolines/chemistry ; Limit of Detection ; },
abstract = {As a neurodegenerative disorder, Alzheimer's disease (AD) is characterized by cognitive dysfunction and behavioral impairment. Among the various genetic risk factors for AD, apoE4 gene plays a pivotal role in the onset and progression of AD, and detection of apoE4 gene holds significance for prevention and early diagnosis of AD. Herein, dual-signal fluorescence detection of fragments associated with apoE ε4 allele near codon 112 (Tc1) and codon 158 (Tc2) was achieved using DNA tetrahedron nanostructure (DTN). The Förster resonance energy transfer (FRET) process in the DTN was initiated in which the nucleic acid intercalating dye thiazole orange (TO) served as the donor and the cyanine dyes of cyanine3 (Cy3) and cyanine5 (Cy5) at the two vertices of DTN served as the acceptors. In the presence of Tc1 and Tc2, the FRET process between TO and the cyanine dyes was hindered by the enzymatic cleavage reaction, which ensures the dual-signal fluorescence assay of apoE4 gene sites. The limit of detection for Tc1 and Tc2 was estimated to be 0.82 nM and 0.77 nM, respectively, and the whole assay was accomplished within 1 h on a microplate reader. The proposed method thus possesses the advantages of easy operation, short detection time, and high-throughput capability.},
}

*Apolipoprotein E4/genetics
*Fluorescence Resonance Energy Transfer/methods
Humans
*Fluorescent Dyes/chemistry
*DNA/chemistry/genetics
*Carbocyanines/chemistry
Benzothiazoles/chemistry
Nanostructures/chemistry
Quinolines/chemistry
Limit of Detection

@article {pmid38670598,
year = {2024},
author = {Yang, A and Yi, X and Zhang, H and Shen, R and Kou, X},
title = {Diosmetin derivatives as multifunctional anti-AD ligands: Design, synthesis, and biological evaluation.},
journal = {Chemical biology & drug design},
volume = {103},
number = {4},
pages = {e14529},
doi = {10.1111/cbdd.14529},
pmid = {38670598},
issn = {1747-0285},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry/metabolism ; *Acetylcholinesterase/metabolism ; Animals ; *Butyrylcholinesterase/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Drug Design ; *Caenorhabditis elegans/drug effects/metabolism ; *Molecular Docking Simulation ; Ligands ; *Blood-Brain Barrier/metabolism ; Humans ; *Reactive Oxygen Species/metabolism ; *Flavonoids/chemistry/pharmacology/chemical synthesis ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; Protein Aggregates/drug effects ; },
abstract = {With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1-4) were designed, synthesized, and characterized by [1]H NMR, [13]C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and β-amyloid (Aβ) aggregation inhibition in vitro were evaluated. The results showed that 1-4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu[2+] ions), antioxidation, self-induced, Cu[2+]-induced, and AChE-induced Aβ aggregation inhibition activities, and suitable blood-brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10[-8] M magnitude) and BuChE (10[-7] M magnitude) and showed the best inhibition on AChE-induced Aβ aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.},
}

*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry/metabolism
*Acetylcholinesterase/metabolism
Animals
*Butyrylcholinesterase/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Drug Design
*Caenorhabditis elegans/drug effects/metabolism
*Molecular Docking Simulation
Ligands
*Blood-Brain Barrier/metabolism
Humans
*Reactive Oxygen Species/metabolism
*Flavonoids/chemistry/pharmacology/chemical synthesis
Antioxidants/pharmacology/chemistry/chemical synthesis
Structure-Activity Relationship
Protein Aggregates/drug effects

@article {pmid38670534,
year = {2024},
author = {Ding, Y and Lin, M and Wang, J and Shang, X},
title = {RBM3 enhances the stability of MEF2C mRNA and modulates blood-brain barrier permeability in AD microenvironment.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {},
number = {},
pages = {119738},
doi = {10.1016/j.bbamcr.2024.119738},
pmid = {38670534},
issn = {1879-2596},
abstract = {Blood-brain barrier (BBB) changes are acknowledged as early indicators of Alzheimer's disease (AD). The permeability and integrity of the blood-brain barrier (BBB) rely significantly on the essential role played by the tight junction proteins (TJPs) connecting endothelial cells. This study found the reduced RNA binding motif protein 3 (RBM3) expression in brain microvascular endothelial cells (BMECs) incubated with Aβ1-42. This downregulation of RBM3 caused a decrease in the levels of ZO-1 and occludin and increased the permeability of BBB cell model in AD microenvironment. Myocyte enhancer factor 2C (MEF2C) expression was also inhibited in BMECs incubated with Aβ1-42. A decrease in MEF2C expression led to increased permeability of BBB cell model in AD microenvironment and reductions in the levels of ZO-1 and occludin. Further analysis of the underlying mechanism revealed that RBM3 binds to and stabilizes MEF2C mRNA. MEF2C binds to the promoters of ZO-1 and occludin, enhancing their transcriptional activities and modulating BBB permeability. RBM3 increases the stability of MEF2C mRNA and subsequently modulates BBB permeability through the paracellular pathway of TJPs. This may provide new insights for AD research.},
}

@article {pmid38670478,
year = {2024},
author = {Xie, Y and Li, X and Shi, Q and Le, L and Wang, C and Xu, H and Wu, G and Du, X and Chen, Z},
title = {The synergistic effect of curcumin and mitoquinol mesylate on cognitive impairment and the neuropathology of Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {148959},
doi = {10.1016/j.brainres.2024.148959},
pmid = {38670478},
issn = {1872-6240},
abstract = {Given the complexity and heterogeneity of Alzheimer's disease (AD) pathology, targeted monotherapies drug may not be effective. Therefore, a synergistic combination therapy of curcumin and Mito Q was proposed and evaluated in a triple-transgenic AD model mice (3 × Tg-AD mice). The cognitive ability was assessed using behavioral tests and typical pathological changes were observed through Western blotting and histological analysis. The results demonstrated a significant enhancement in cognitive ability along with the mitigation of typical AD pathological features such as Aβ aggregation, tau phosphorylation, and synaptic damage. Notably, the combination therapy demonstrated superior efficacy over individual drugs alone. These findings provide valuable insights for optimizing the development of AD drugs.},
}

@article {pmid38670398,
year = {2024},
author = {Sengupta, P and Sen, S and Mukhopadhyay, D},
title = {The receptor tyrosine kinase IGF1R and its associated GPCRs are co-regulated by the noncoding RNA NEAT1 in Alzheimer's disease.},
journal = {Gene},
volume = {},
number = {},
pages = {148503},
doi = {10.1016/j.gene.2024.148503},
pmid = {38670398},
issn = {1879-0038},
abstract = {The study is based on the complexity of Insulin like growth factor receptor (IGF1R) signaling and its regulation by noncoding RNAs (ncRNAs). IGF1R signaling is an important cascade in Alzheimer's disease (AD); however, its regulation and roles are poorly understood. Due to the presence of β-arrestin and GPCR Receptor Kinase binding sites, this protein has been termed a 'functional hybrid', as it can take part in both kinase and GPCR signaling pathways, further adding to its complexity. The objective of this study is to understand the underlying ncRNA regulation controlling IGF1R and GPCRs in AD to find commonalities in the network. We found through data mining that 45 GPCRs were reportedly deregulated in AD and built clusters based on GO/KEGG pathways to show shared functionality with IGF1R. Eight miRs were further discovered that could coregulate IGF1R and GPCRs. We validated their expression in an AD cell model and probed for common lncRNAs downstream that could regulate these miRs. Seven such candidates were identified and further validated. A combined network comprising IGF1R with nine GPCRs, eight miRs, and seven lncRNAs was created to visualize the interconnectivity within pathways. Betweenness centrality analysis showed a cluster of NEAT1, hsa-miR-15a-5p, hsa-miR-16-5p, and IGF1R to be crucial form a competitive endogenous RNA-based (ceRNA) tetrad that could relay information within the network, which was further validated by cell-based studies. NEAT1 emerged as a master regulator that could alter the levels of IGF1R and associated GPCRs. This combined bioinformatics and experimental study for the first time explored the regulation of IGF1R through ncRNAs from the perspective of neurodegeneration.},
}

@article {pmid38670299,
year = {2024},
author = {Sharma, M and Tanwar, AK and Purohit, PK and Pal, P and Kumar, D and Vaidya, S and Prajapati, SK and Kumar, A and Dhama, N and Kumar, S and Gupta, SK},
title = {REGULATORY ROLES OF microRNAs IN MODULATING MITOCHONDRIAL DYNAMICS, AMYLOID BETA FIBRILLATION, MICROGLIAL ACTIVATION, AND CHOLINERGIC SIGNALING: IMPLICATIONS FOR ALZHEIMER'S DISEASE PATHOGENESIS.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {105685},
doi = {10.1016/j.neubiorev.2024.105685},
pmid = {38670299},
issn = {1873-7528},
abstract = {Alzheimer's Disease (AD) remains a formidable challenge due to its complex pathology, notably involving mitochondrial dysfunction and dysregulated microRNA (miRNA) signaling. This study delves into the underexplored realm of miRNAs' impact on mitochondrial dynamics and their interplay with amyloid-beta (Aβ) aggregation and tau pathology in AD. Addressing identified gaps, our research utilizes advanced molecular techniques and AD models, alongside patient miRNA profiles, to uncover miRNAs pivotal in mitochondrial regulation. We illuminate novel miRNAs influencing mitochondrial dynamics, Aβ, and tau, offering insights into their mechanistic roles in AD progression. Our findings not only enhance understanding of AD's molecular underpinnings but also spotlight miRNAs as promising therapeutic targets. By elucidating miRNAs' roles in mitochondrial dysfunction and their interactions with hallmark AD pathologies, our work proposes innovative strategies for AD therapy, aiming to mitigate disease progression through targeted miRNA modulation. This contribution marks a significant step toward novel AD treatments, emphasizing the potential of miRNAs in addressing this complex disease.},
}

@article {pmid38670277,
year = {2024},
author = {Rodrigues, MES and Bolen, ML and Blackmer-Raynolds, L and Schwartz, N and Chang, J and Tansey, MG and Sampson, TR},
title = {Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106511},
doi = {10.1016/j.nbd.2024.106511},
pmid = {38670277},
issn = {1095-953X},
abstract = {Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.},
}

@article {pmid38670235,
year = {2024},
author = {Bartels, CM and Chen, Y and Powell, WR and Rosenkranz, MA and Bendlin, BB and Kramer, J and Busse, WW and Kind, A},
title = {Alzheimer's Incidence and Prevalence with and without Asthma: A Medicare cohort study.},
journal = {The Journal of allergy and clinical immunology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaci.2024.04.008},
pmid = {38670235},
issn = {1097-6825},
abstract = {BACKGROUND: International data suggest that asthma, like other inflammatory diseases, might increase Alzheimer's disease (AD) risk.

OBJECTIVE: To explore risk pathways and future mitigation strategies by comparing diagnostic claims-based AD incidence and prevalence among US patients with asthma to non-asthma patients.

METHODS: This cohort study included a national Medicare 20% random sample 2013-2015. Adult patients with >12 months continuous Medicare with asthma were compared to non-asthma subjects overall and as matched. Asthma was defined by one inpatient or two outpatient codes for asthma. The main outcomes were two-year incident or prevalent AD defined as any codes for ICD-9 331.0 or ICD-10 G30.0, G30.1, G30.8, G30.9.

RESULTS: Among 5,460,732 total beneficiaries, 678,730 patients were identified with baseline asthma and more often identified as Black or Hispanic, were Medicaid eligible, or resided in a highly disadvantaged neighborhood than those without asthma. Two-year incidence of AD was 1.4% with asthma vs 1.1% without; prevalence was 7.8% vs 5.4% (both p=<0.001). Per 100,000 patients over two years, 303 more incident AD diagnoses occurred in asthma, with 2,425 more prevalent cases (p<0.001). Multivariable models showed asthma had greater odds of two-year AD incidence [AOR 1.33 (1.29-1.36); matched 1.2 (1.17-1.24)] and prevalence [AOR 1.48 (1.47-1.50); matched 1.25 (1.22-1.27)).

CONCLUSION: Asthma was associated with 20-33% increased two-year incidence and 25-48% increased prevalence of claims-based Alzheimer's disease in this nationally representative US sample. Future research should investigate risk pathways of underlying comorbidities and social determinants, as well as whether there are potential asthma treatments that may preserve brain health.},
}