@article {pmid39044044,
year = {2024},
author = {Supti, ST and Koehn, LM and Newman, SA and Pan, Y and Nicolazzo, JA},
title = {Iron Reduces the Trafficking of Fatty Acids from Human Immortalised Brain Microvascular Endothelial Cells Through Modulation of Fatty Acid Transport Protein 1 (FATP1/SLC27A1).},
journal = {Pharmaceutical research},
volume = {},
number = {},
pages = {},
pmid = {39044044},
issn = {1573-904X},
abstract = {PURPOSE: Alzheimer's disease (AD) is associated with brain accumulation of amyloid-beta (Aβ) and neurofibrillary tangle formation, in addition to reduced brain docosahexaenoic acid (DHA) and increased brain iron levels. DHA requires access across the blood-brain barrier (BBB) to enter the brain, and iron has been shown to affect the expression and function of a number of BBB transporters. Therefore, this study aimed to assess the effect of iron on the expression and function of fatty acid binding protein 5 (FABP5) and fatty acid transport protein 1 (FATP1), both which mediate brain endothelial cell trafficking of DHA.

METHODS: The mRNA and protein levels of FABP5 and FATP1 in human cerebral microvascular endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively following ferric ammonium citrate (FAC) treatment (up to 750 µM, 72 h). The function of FABP5 and FATP1 was assessed via uptake and efflux of radiolabelled [3]H-oleic acid and [14]C-DHA.

RESULTS: FAC (500 µM, 72 h) had no impact on the expression of FABP5 at the protein and mRNA level in hCMEC/D3 cells, which was associated with a lack of effect on the uptake of [14]C-DHA. FAC led to a 19.7% reduction in FATP1 protein abundance in hCMEC/D3 cells with no impact on mRNA levels, and this was associated with up to a 32.6% reduction in efflux of [14]C-DHA.

CONCLUSIONS: These studies demonstrate a role of iron in down-regulating FATP1 protein abundance and function at the BBB, which may have implications on fatty acid access to the brain.},
}

@article {pmid39042202,
year = {2024},
author = {de Paiva, IHR and da Silva, RS and Mendonça, IP and de Souza, JRB and Peixoto, CA},
title = {Semaglutide Attenuates Anxious and Depressive-Like Behaviors and Reverses the Cognitive Impairment in a Type 2 Diabetes Mellitus Mouse Model Via the Microbiota-Gut-Brain Axis.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {19},
number = {1},
pages = {36},
pmid = {39042202},
issn = {1557-1904},
support = {PROEP#400208/2019-9//Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz/ ; VPPCB-007-FIO-18-2-17//Fundação Oswaldo Cruz/ ; #301777/2012-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Animals ; *Glucagon-Like Peptides/pharmacology ; *Diabetes Mellitus, Type 2/complications/drug therapy/psychology/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/prevention & control/etiology/metabolism ; *Depression/drug therapy/psychology/metabolism ; Male ; *Anxiety/drug therapy/psychology/etiology ; *Gastrointestinal Microbiome/drug effects ; *Mice, Inbred C57BL ; *Brain-Gut Axis/drug effects ; Diabetes Mellitus, Experimental/complications/drug therapy/psychology/metabolism ; Disease Models, Animal ; Antidepressive Agents/pharmacology/therapeutic use ; },
abstract = {Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.},
}

Animals
*Glucagon-Like Peptides/pharmacology
*Diabetes Mellitus, Type 2/complications/drug therapy/psychology/metabolism
Mice
*Cognitive Dysfunction/drug therapy/prevention & control/etiology/metabolism
*Depression/drug therapy/psychology/metabolism
Male
*Anxiety/drug therapy/psychology/etiology
*Gastrointestinal Microbiome/drug effects
*Mice, Inbred C57BL
*Brain-Gut Axis/drug effects
Diabetes Mellitus, Experimental/complications/drug therapy/psychology/metabolism
Disease Models, Animal
Antidepressive Agents/pharmacology/therapeutic use

@article {pmid39041662,
year = {2024},
author = {Chen, H and Gao, X and Li, X and Yu, C and Liu, W and Qiu, J and Liu, W and Geng, H and Zheng, F and Gong, H and Xu, Z and Jia, J and Zhao, Q},
title = {Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer's Disease.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.4c00483},
pmid = {39041662},
issn = {1520-4804},
abstract = {Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.},
}

@article {pmid39041342,
year = {2024},
author = {Biswas, S and Chowdhury, T and Banerjee, S and Dutta, K and Das, AK and Das, D},
title = {Improving the Efficiency of Luminescent Zn(II)-Modified N-Doped GOQD Nanomaterials in Parkinson's Disease Treatment: A Theoretical Mechanistic Framework Exploring Doping Effect.},
journal = {Chemistry, an Asian journal},
volume = {},
number = {},
pages = {e202400629},
doi = {10.1002/asia.202400629},
pmid = {39041342},
issn = {1861-471X},
abstract = {Levodopa, a widely prescribed drug in Parkinson's disease treatment, stands as the foremost prodrug of dopamine. An affordable self-testing kit is utilized to monitor levodopa content in anti-parkinson drugs in human serum. A photoluminescent trinuclear Zn(II) complex [Zn3(L)2(κ1-OAc)2(κ2-OAc)2] has been synthesized, which cleaves into mononuclear ZC in aqueous solution. ZC was found to detect L-Dopa in Tris-HCl buffer, exhibiting a moderate decrease in PL-emission. The real-life utility of the ZC probe is limited, for its lower sensitivity (LOD 35.3 µM) and separation challenges. Therefore, an interface between homogeneous and heterogeneous supports has been explored, leading to the strategic development of NGOZC, where ZC was grafted onto NGOQD. This material enables naked- eye detection under both ambient and UV light with color change from bright cyan to green, followed by dark. The nitrogen doping effect was investigated by several comparative investigations involving the synthesis of ZC-grafted GOQD, leading to enhanced quenching performance. Steady-state and time-resolved fluorescence titration study, morphological analysis, and computational calculations have been performed to get insights into the sensing mechanism. To the best of our knowledge, this as-synthesized NGOZC (LOD 1.78 nM) represents a promising strategy and platform for applications in biosensors, especially for Parkinson's and Alzheimer's diseases.},
}

@article {pmid39041310,
year = {2024},
author = {Magana-Ramirez, CM and Irizarry-Martinez, G and Gillen, DL and Grill, JD},
title = {Reasons for undergoing amyloid imaging among diverse enrollees in the A4 study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14077},
pmid = {39041310},
issn = {1552-5279},
support = {DGE-1839285//The National Science Foundation's Graduate Research Fellowship/ ; P30 AG066519/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Understanding attitudes toward participation among diverse preclinical Alzheimer's disease (AD) trial participants could yield insights to instruct future recruitment.

METHODS: Using data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study, we examined differences among mutually exclusive racial and ethnic groups in views and perceptions of amyloid imaging (VPAI), a measure of motivations to undergo amyloid biomarker testing in the setting of preclinical AD. We used linear regression to quantify differences at baseline.

RESULTS: Compared to non-Hispanic or Latino (NH) White participants, Hispanic or Latino (3.52 points, 95% confidence interval [CI]: [2.61, 4.42]); NH Asian (2.97 points, 95% CI: [1.71, 4.22]); and NH Black participants (2.79 points, 95% CI: [1.96, 3.63]) participants demonstrated higher levels of endorsement of the VPAI items at baseline.

DISCUSSION: Differences may exist among participants from differing ethnic and racial groups in motivations to undergo biomarker testing in the setting of a preclinical AD trial.

HIGHLIGHTS: Representative samples in AD clinical trials are vital to result in generalizability. We assessed motivations to undergo amyloid imaging in a preclinical AD trial. Racial and ethnic minority groups showed higher endorsement of VPAI items. Differences were driven by perceived risk, plan/prepare, and curiosity domains. Few observations among racial and ethnic groups changed after biomarker disclosure.},
}

@article {pmid39041170,
year = {2024},
author = {Wu, QY and Xu, XG and Zhang, QY and Huang, SH and Zhang, DL},
title = {[Analysis of current situation of outcome indicators in randomized controlled trials on traditional Chinese medicine in treatment of Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {49},
number = {11},
pages = {3113-3124},
doi = {10.19540/j.cnki.cjcmm.20240218.501},
pmid = {39041170},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Randomized Controlled Trials as Topic ; *Drugs, Chinese Herbal/therapeutic use ; *Medicine, Chinese Traditional ; Treatment Outcome ; Aged ; },
abstract = {This study aims to analyze the current situation of outcome indicators in randomized controlled trial(RCT) of traditional Chinese medicine(TCM) treatment for Alzheimer's disease(AD), so as to provide a reference for establishing a core indicator set in this field. The researchers systematically searched CNKI, Wanfang, VIP, Sino Med, EMbase, PubMed, Medline, and Cochrane Library. Independent screening of literature and extraction of information was conducted according to the inclusion and exclusion criteria. In addition, the Ro B 2. 0 tool was used for bias risk assessment. A total of 78 RCTs were included, involving 6 379 patients,with 122 kinds of outcome indicators. According to functional attributes, the outcome indicators could be categorized into seven groups:TCM diseases(3 kinds, 13 times), symptoms and signs(26 kinds, 196 times), physical and chemical tests(68 kinds, 149 times),qua-lity of life(1 kind, 2 times), long-term prognosis(2 kinds, 2 times), economic evaluation(0 kind), safety events(21 kinds,194 times), and other indicators(1 kind, 1 time). The results show that the literature evaluation of RCTs of TCM treatment for AD is generally risky, and there are some problems in the selection of outcome indicators, such as lack of TCM characteristics, insignificant distinction between primary and secondary outcome indicators, lack of long-term prognosis and economic evaluation indicators, and non-standard safety event reports. It is suggested that future researchers should establish a core indicator set for AD that highlights the characteristics of TCM and then work to improve the quality of clinical trials.},
}

*Alzheimer Disease/drug therapy
Humans
*Randomized Controlled Trials as Topic
*Drugs, Chinese Herbal/therapeutic use
*Medicine, Chinese Traditional
Treatment Outcome
Aged

@article {pmid39040546,
year = {2024},
author = {Rentsch, P and Ganesan, K and Langdon, A and Konen, LM and Vissel, B},
title = {Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1421900},
pmid = {39040546},
issn = {1663-4365},
abstract = {BACKGROUND: Finding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance.

METHODS: In the current study, we exposed humanized Aβ knock-in mice (hAβ-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice.

RESULTS: At the early time point of 24 weeks, hAβ-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAβ-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aβ plaques in hAβ-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAβ-KI mice compared to WT, and LPS exposure in hAβ-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology.

CONCLUSION: The study highlights the potential of hAβ-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aβ plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.},
}

@article {pmid39040486,
year = {2024},
author = {Honda Pazili, T},
title = {A Severe Alzheimer's Disease Patient Improved by Intravenous Mesenchymal Stem Cell Transplant.},
journal = {Case reports in neurological medicine},
volume = {2024},
number = {},
pages = {8353492},
pmid = {39040486},
issn = {2090-6668},
abstract = {Alzheimer's disease (AD) is a progressive neurological disorder and is the most common form of dementia. The terminal stage of AD is characterized by severe cognitive and substantial functional decline, requiring extensive assistance with daily activities. As effective therapies at this stage are not fully available, development of therapeutics that can recover any symptoms would be important to improve the quality of life. Recently, stem cell therapy has gathered a lot of attention in several neurological diseases, including AD. Here, we report an AD patient at the terminal stage whose symptoms were improved by the intravenous administration of ex vivo-expanded bone marrow-derived mesenchymal stem cells (MSC). The case is a 61-year-old woman with severe Alzheimer's disease who had been admitted to the special nursing home. She could neither walk nor sit up independently. She also did neither smile nor gaze properly when talked to. Rigidity including neck motion was observed. She was on dysphagia diets. We cultured her bone-marrow-derived MSCs and intravenously administered 1,5 × 10[8] cells. After the treatment, smile loss, eye movement dysfunction, and neck immobility were improved. This is the first case report that showed the therapeutic effects of MSCs on terminal symptoms of AD.},
}

@article {pmid39040206,
year = {2024},
author = {Meng, W and Xu, J and Huang, Y and Wang, C and Song, Q and Ma, A and Song, L and Bian, J and Ma, Q and Yin, R},
title = {Autoencoder to Identify Sex-Specific Sub-phenotypes in Alzheimer's Disease Progression Using Longitudinal Electronic Health Records.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.07.24310055},
pmid = {39040206},
abstract = {Alzheimer's Disease (AD) is a complex neurodegenerative disorder significantly influenced by sex differences, with approximately two-thirds of AD patients being women. Characterizing the sex-specific AD progression and identifying its progression trajectory is a crucial step to developing effective risk stratification and prevention strategies. In this study, we developed an autoencoder to uncover sex-specific sub-phenotypes in AD progression leveraging longitudinal electronic health record (EHR) data from OneFlorida+ Clinical Research Consortium. Specifically, we first constructed temporal patient representation using longitudinal EHRs from a sex-stratified AD cohort. We used a long short-term memory (LSTM)-based autoencoder to extract and generate latent representation embeddings from sequential clinical records of patients. We then applied hierarchical agglomerative clustering to the learned representations, grouping patients based on their progression sub-phenotypes. The experimental results show we successfully identified five primary sex-based AD sub-phenotypes with corresponding progression pathways with high confidence. These sex-specific sub-phenotypes not only illustrated distinct AD progression patterns but also revealed differences in clinical characteristics and comorbidities between females and males in AD development. These findings could provide valuable insights for advancing personalized AD intervention and treatment strategies.},
}

@article {pmid39040111,
year = {2024},
author = {Liao, Z and Zhang, Q and Ren, N and Zhao, H and Zheng, X},
title = {Progress in mitochondrial and omics studies in Alzheimer's disease research: from molecular mechanisms to therapeutic interventions.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1418939},
pmid = {39040111},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Mitochondria/metabolism ; Animals ; Genomics/methods ; Energy Metabolism ; Proteomics/methods ; },
abstract = {Alzheimer's disease (Alzheimer's disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and β-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*Mitochondria/metabolism
Animals
Genomics/methods
Energy Metabolism
Proteomics/methods

@article {pmid39040086,
year = {2024},
author = {Liu, F and Li, H and Hong, X and Liu, Y and Yu, Z},
title = {Research progress of neuron-specific enolase in cognitive disorder: a mini review.},
journal = {Frontiers in human neuroscience},
volume = {18},
number = {},
pages = {1392519},
pmid = {39040086},
issn = {1662-5161},
abstract = {Numerous studies have demonstrated that neuron-specific enolase (NSE) serves as a distinctive indicator of neuronal injury, with its concentration in blood reflecting the extent and magnitude of nervous system damage, and the expression of serum NSE is correlated with cognitive dysfunction. The assessment of NSE holds significant importance in diagnosing cognitive dysfunction, assessing disease severity, predicting prognosis, and guiding treatment. In this review, the research progress of NSE in cognitive dysfunction was reviewed, and the value of serum NSE level in predicting disease severity and prognosis of patients with cognitive dysfunction was discussed.},
}

@article {pmid39039684,
year = {2024},
author = {Kolay, A and Singh, N and Gupta, P and Shaikh, AM and Goel, R and Nagpal, D and Chitme, H},
title = {Immunotherapies: A Treasure Trove of Alzheimer's Disease.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010308600240709052539},
pmid = {39039684},
issn = {1873-4316},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease that falls under the umbrella of dementia and is characterized by the presence of enormously neurotoxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein inside the brain. AD remains an intractable global health challenge with limited therapeutic options. Early diagnosis, enabled by biomarkers and neuroimaging, is pivotal for optimizing treatment outcomes. Immunotherapeutic strategies, including monoclonal antibodies, active vaccination, and passive immunization, have been developed to target hallmark AD pathology, such as amyloid-beta aggregation. Here we summarized the emerging role of immunotherapies in the early stages of AD, shedding light on recent breakthroughs and clinical progress. Challenges, including treatment response variability and safety concerns, are discussed alongside evolving approaches, such as personalized immunotherapy and combinatorial treatments. This concise review underscores the promise of immunotherapies as a transformative approach to AD intervention, offering hope for a brighter future in the quest to combat this devastating neurodegenerative disease.},
}

@article {pmid39039673,
year = {2024},
author = {Rathee, S and Sen, D and Pandey, V and Jain, SK},
title = {Advances in Understanding and Managing Alzheimer's Disease: From Pathophysiology to Innovative Therapeutic Strategies.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501320096240627071400},
pmid = {39039673},
issn = {1873-5592},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the presence of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles, leading to cognitive and physical decline. Representing the majority of dementia cases, AD poses a significant burden on healthcare systems globally, with onset typically occurring after the age of 65. While most cases are sporadic, about 10% exhibit autosomal forms associated with specific gene mutations. Neurofibrillary tangles and Aβ plaques formed by misfolded tau proteins and Aβ peptides contribute to neuronal damage and cognitive impairment. Currently, approved drugs, such as acetylcholinesterase inhibitors and N-methyl D-aspartate receptor agonists, offer only partial symptomatic relief without altering disease progression. A promising development is using lecanemab, a humanized IgG1 monoclonal antibody, as an immune therapeutic approach. Lecanemab demonstrates selectivity for polymorphic Aβ variants and binds to large soluble Aβ aggregates, providing a potential avenue for targeted treatment. This shift in understanding the role of the adaptive immune response in AD pathogenesis opens new possibilities for therapeutic interventions aiming to address the disease's intricate mechanisms. This review aims to summarize recent advancements in understanding Alzheimer's disease pathology and innovative therapeutic approaches, providing valuable insights for both researchers and clinicians.},
}

@article {pmid39039061,
year = {2024},
author = {Du, Y and Zhang, S and Qiu, Q and Fang, Y and Zhao, L and Yue, L and Wang, J and Yan, F and Li, X},
title = {The mediating effect of the amygdala-frontal circuit on the association between depressive symptoms and cognitive function in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {14},
number = {1},
pages = {301},
pmid = {39039061},
issn = {2158-3188},
mesh = {Humans ; *Amygdala/physiopathology/diagnostic imaging ; *Alzheimer Disease/physiopathology/diagnostic imaging/psychology ; Male ; Female ; Aged ; *Depression/physiopathology/diagnostic imaging ; *Cognition ; Middle Aged ; Diffusion Tensor Imaging ; Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology ; Frontal Lobe/physiopathology/diagnostic imaging ; Neural Pathways/physiopathology ; Case-Control Studies ; Magnetic Resonance Imaging ; Prefrontal Cortex/diagnostic imaging/physiopathology ; },
abstract = {Depressive symptoms occur commonly in Alzheimer's disease (AD). Although abnormalities in the amygdala-frontal circuit have been linked to emotional dysregulation and cognitive impairment, the neurological basis underlying these associations in AD patients with depressive symptoms (ADD) is unclear. We aimed to investigate the relationship between the amygdala-frontal circuit and depressive symptoms and cognitive function in ADD. We recruited 60 ADD, 60 AD patients without depressive symptoms (ADND), and 60 healthy controls (HC). Functional connectivity (FC) maps of the bilateral amygdala were compared. Fractional anisotropy (FA) of the amygdala-frontal circuit connected by the uncinate fasciculus (UF) was calculated using automated fiber quantification (AFQ). In addition, mediation analysis was performed to explore the effects of the amygdala-frontal circuit on the relationship between depressive symptoms and cognitive function. We found decreased bilateral amygdala FC with the inferior frontal gyrus (IFG) in the ADD group compared to the ADND and HC groups. Moreover, FA in the left frontal UF (nodes 64-97) was significantly lower in the ADD group than ADND group. Notably, amygdala-based FC with IFG and the left frontal UF FA mediated the relationship between depressive symptoms and cognitive function in ADD, with mediating effects ranging between 15 and 18%. Our study is the first to demonstrate the mediating effect of functional and microstructural abnormalities in the amygdala-frontal circuit in ADD. The findings suggest that the amygdala-frontal circuit may underlie emotional dysregulation in ADD, providing potential targets for treatment strategies.},
}

Humans
*Amygdala/physiopathology/diagnostic imaging
*Alzheimer Disease/physiopathology/diagnostic imaging/psychology
Male
Female
Aged
*Depression/physiopathology/diagnostic imaging
*Cognition
Middle Aged
Diffusion Tensor Imaging
Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology
Frontal Lobe/physiopathology/diagnostic imaging
Neural Pathways/physiopathology
Case-Control Studies
Magnetic Resonance Imaging
Prefrontal Cortex/diagnostic imaging/physiopathology

@article {pmid39038637,
year = {2024},
author = {Ansari, MM and Sahu, SK and Singh, TG and Singh, S and Kaur, P},
title = {Evolving Significance of Kinase Inhibitors in the Management of Alzheimer's Disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {176816},
doi = {10.1016/j.ejphar.2024.176816},
pmid = {39038637},
issn = {1879-0712},
abstract = {Alzheimer's disease is a neurodegenerative problem with progressive loss of memory and other cognitive function disorders resulting in the imbalance of neurotransmitter activity and signaling progression, which poses the need of the potential therapeutic target to improve the intracellular signaling cascade brought by kinases. Protein kinase plays a significant and multifaceted role in the treatment of Alzheimer's disease, by targeting pathological mechanisms like tau hyperphosphorylation, neuroinflammation, amyloid-beta production and synaptic dysfunction. In this review, we thoroughly explore the essential protein kinases involved in Alzheimer's disease, detailing their physiological roles, regulatory impacts, and the newest inhibitors and compounds that are progressing into clinical trials. All the findings of studies exhibited the promising role of kinase inhibitors in the management of Alzheimer's disease. However, it still poses the need of addressing current challenges and opportunities involved with this disorder for the future perspective of kinase inhibitors in the management of Alzheimer's disease. Further study includes the development of biomarkers, combination therapy, and next-generation kinase inhibitors with increased potency and selectivity for its future prospects.},
}

@article {pmid39038355,
year = {2024},
author = {Dong, C and Xue, F and Ji, X and Zhang, D},
title = {Analysis and Research on the Relationship between Oral Microorganisms and Alzheimer's Disease.},
journal = {Alternative therapies in health and medicine},
volume = {},
number = {},
pages = {},
pmid = {39038355},
issn = {1078-6791},
abstract = {BACKGROUND: The common neurodegenerative disease among the elderly is Alzheimer's disease, which in severe cases can affect the quality of life of patients and their families. It has been reported that oral microorganisms are involved in the progression of Alzheimer's disease.

OBJECTIVE: To analyze the relationship between oral microorganisms and Alzheimer's disease.

METHODS: The oral microbial population, a comprehensive analysis of relevant literature was conducted. Immunofluorescence was adopted to assess albumin deposition in the cerebral cortex of mice. Western blot was used to detect expression level of CYP46 in mouse brain.

RESULTS: It can be concluded that the population of oral microorganisms includes bacteria, viruses, fungi, and spirochetes, which can cause various oral diseases. They can enter the human brain through the blood and surrounding nerves, leading to permeability increase of the blood-brain barrier and neuroimmune related inflammation. They will participate in and worsen the pathological process of Alzheimer's disease, leading to damage to neurons and cerebral blood vessels. The intervention methods for oral microbiota population include vaccination and phage therapy. Vaccines provide suitable treatment methods for periodontal disease, and phage therapy is a new method for controlling oral infections. At the same time, postoperative patients with oral diseases can use gel containing ethanol extract of Brazilian green propolis to ensure oral hygiene. In the rat blood-brain barrier model, porphyromonas gingivalis bacteremia enhanced barrier permeability, and immunofluorescence showed an increase in albumin deposition in the rat cerebral cortex. The expression of cytochrome P450 46A1 (CYP46A1) enzyme in the brain of Alzheimer's disease mice aged 24-56 weeks after long-term administration of SLAB51 increased.

CONCLUSION: The elderly population should develop good living habits, maintain a clean mouth, and adjust the oral environment through methods such as oral and Alzheimer's disease promotion, combined with medication treatment.},
}

@article {pmid39037949,
year = {2024},
author = {Laghchioua, FE and da Silva, CFM and Pinto, DCGA and Cavaleiro, JAS and Mendes, RF and Paz, FAA and Faustino, MAF and Rakib, EM and Neves, MGPMS and Pereira, F and Moura, NMM},
title = {Design of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insights.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00241},
pmid = {39037949},
issn = {1948-7193},
abstract = {Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 μM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 μM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.},
}

@article {pmid39037747,
year = {2024},
author = {Mattke, S and Ozawa, T and Hanson, M},
title = {Implications of treatment duration and frequency for value and cost-effective price of Alzheimer treatments.},
journal = {Journal of managed care & specialty pharmacy},
volume = {},
number = {},
pages = {1-8},
doi = {10.18553/jmcp.2024.24116},
pmid = {39037747},
issn = {2376-1032},
abstract = {BACKGROUND: Disease-modifying Alzheimer treatments are becoming available. The value of the treatments will be attenuated by their complexity of delivery and monitoring, creating additional medical cost and caregiver burden.

OBJECTIVE: To estimate net treatment value using different assumptions for treatment duration and intensity.

METHODS: We estimated the lifetime value of hypothetical treatments that reduce disease progression by 30% from a payer perspective, which considers cost offsets, i.e., reduced medical and formal social care costs, and quality-adjusted life-year gains, and a societal perspective, which adds reduction in caregiver burden. Estimates for gross value of the treatment were based on a prior publication, medical cost on Medicare payment rates, and caregiver time use on a survey of 21 clinics. We analyzed 5 hypothetical treatment scenarios: treatment until progression to moderate dementia with (1) biweekly and (2) 4-weekly infusions, and time-limited infusions every 4 weeks for (3) 72, (4) 52, and (5) 24 weeks.

RESULTS: Treatment until progression to moderate dementia would take 5.7 years and generate gross value of $20,734 in direct cost offsets, $83,761 from a payer and $87,749 from a societal perspective, respectively. Added medical cost and caregiver burden for the 5 scenarios would be $44,179, $24,875, $21,632, $20,416, and $14,350, respectively. The maximum value-based price per year would be $7,687, $11,088, $47,708, $67,273, and $158,954.

CONCLUSIONS: Assuming identical efficacy and safety, the net value generation of time-limited treatment is projected to be larger than that of chronic treatment. Such determination of net lifetime value can be useful to determine value-based prices for different treatment types.},
}

@article {pmid39037560,
year = {2024},
author = {Li, C and Zhao, X and Xu, H and Liu, X and He, Y and Gu, J},
title = {NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {},
number = {},
pages = {},
pmid = {39037560},
issn = {1573-6903},
support = {202019191//Clinical Medical Science and Technology Innovation Program of Jinan/ ; QYPY2020NSFC0601//Cultivation Fund for the First Affiliated Hospital of Shandong First Medical University/ ; ZR2021LSW022//Nature Science Joint Foundation of Shandong Province/ ; 2021TSGC1279//Technological SMEs' innovation ability improvement project/ ; },
abstract = {With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-β (Aβ) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aβ deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aβ deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.},
}

@article {pmid39036920,
year = {2024},
author = {Kong, LWY and He, XT and Chen, FM and Li, X},
title = {[Influence of periodontal microbial homeostasis on neurodegenerative diseases and its therapeutic perspectives].},
journal = {Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology},
volume = {59},
number = {8},
pages = {852-857},
doi = {10.3760/cma.j.cn112144-20231027-00225},
pmid = {39036920},
issn = {1002-0098},
support = {82301079, 82371010//National Natural Science Foundation of China/ ; 2022QNRC001//The Young Elite Scientist Sponsorship Program by CAST/ ; },
abstract = {The oral cavity is the second largest reservoir of microorganisms in the human body, containing more than 700 species. Periodontal microorganisms are an important part of oral microorganisms. Plaque biofilm, the initiator of periodontal disease, contains an abundance of oral microorganisms. The special complex anatomy of the periodontium allows for a higher abundance of the periodontal microbiota. There are growing evidences show that the periodontal microbiota is not only closely associated with oral diseases, but also plays an important role in mouth-brain interactions. Dysbiosis of the periodontal microbiota may facilitate the progression of neurodegenerative diseases including Alzheimer disease, Parkinson disease, and multiple sclerosis. Here, this paper reviews the bidirectional role of periodontal microbiota between the oral cavity and the brain, that is, the bridge effect of periodontal microbiota involved in the interaction between the two diseases, enumerates the epidemiological and biological evidences that dysregulation of the periodontal microbiota induces and exacerbates neurodegenerative diseases, and analyzes their possible mechanisms. The positive implications of periodontal microbial homeostasis in the prevention and treatment of neurodegenerative diseases are described with the aim of providing new ideas and insights into the pathogenesis and therapeutic approaches for neurodegenerative diseases.},
}

@article {pmid39036736,
year = {2024},
author = {Kim, B and Kim, YS and Li, W and Kwon, EB and Chung, HS and Go, Y and Choi, JG},
title = {Ginsenoside Rg5, a potent agonist of Nrf2, inhibits HSV-1 infection-induced neuroinflammation by inhibiting oxidative stress and NF-κB activation.},
journal = {Journal of ginseng research},
volume = {48},
number = {4},
pages = {384-394},
pmid = {39036736},
issn = {1226-8453},
abstract = {BACKGROUND: Herpes simplex virus type 1 (HSV-1), known to latently infect the host's trigeminal ganglion, can lead to severe herpes encephalitis or asymptomatic infection, potentially contributing to neurodegenerative diseases like Alzheimer's. The virus generates reactive oxygen species (ROS) that significantly impact viral replication and induce chronic inflammation through NF-κB activation. Nuclear factor E2-related factor 2 (Nrf2), an oxidative stress regulator, can prevent and treat HSV-1 infection by activating the passive defense response in the early stages of infection.

METHODS AND RESULTS: Our study investigated the antiviral effects of ginsenoside Rg5, an Nrf2 activator, on HSV-1 replication and several host cell signaling pathways. We found that HSV-1 infection inhibited Nrf2 activity in host cells, induced ROS/NF-κB signaling, and triggered inflammatory cytokines. However, treatment with ginsenoside Rg5 inhibited ROS/NF-κB signaling and reduced inflammatory cytokines through NRF2 induction. Interestingly, the Nrf2 inhibitor ML385 suppressed the expression of NAD(P)H quinone oxidoreductase 1(NQO1) and enhanced the expression of KEAP1 in HSV-1 infected cells. This led to the reversal of VP16 expression inhibition, a protein factor associated with HSV-1 infection, thereby promoting HSV-1 replication.

CONCLUSION: These findings suggest for the first time that ginsenoside Rg5 may serve as an antiviral against HSV-1 infection and could be a novel therapeutic agent for HSV-1-induced neuroinflammation.},
}

@article {pmid39035166,
year = {2024},
author = {Roytrakul, S and Jaresitthikunchai, J and Phaonakrop, N and Charoenlappanit, S and Thaisakun, S and Kumsri, N and Arpornsuwan, T},
title = {Secretomic changes of amyloid beta peptides on Alzheimer's disease related proteins in differentiated human SH-SY5Y neuroblastoma cells.},
journal = {PeerJ},
volume = {12},
number = {},
pages = {e17732},
pmid = {39035166},
issn = {2167-8359},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Amyloid beta-Peptides/metabolism/pharmacology ; *Neuroblastoma/pathology/metabolism/drug therapy ; Cell Line, Tumor ; *Cell Differentiation/drug effects ; *Brain-Derived Neurotrophic Factor/metabolism/pharmacology ; *tau Proteins/metabolism ; Tretinoin/pharmacology ; Amyloid beta-Protein Precursor/metabolism/genetics ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that causes physical damage to neuronal connections, leading to brain atrophy. This disruption of synaptic connections results in mild to severe cognitive impairments. Unfortunately, no effective treatment is currently known to prevent or reverse the symptoms of AD. The aim of this study was to investigate the effects of three synthetic peptides, i.e., KLVFF, RGKLVFFGR and RIIGL, on an AD in vitro model represented by differentiated SH-SY5Y neuroblastoma cells exposed to retinoic acid (RA) and brain-derived neurotrophic factor (BDNF). The results demonstrated that RIIGL peptide had the least significant cytotoxic activity to normal SH-SY5Y while exerting high cytotoxicity against the differentiated cells. The mechanism of RIIGL peptide in the differentiated SH-SY5Y was investigated based on changes in secretory proteins compared to another two peptides. A total of 380 proteins were identified, and five of them were significantly detected after treatment with RIIGL peptide. These secretory proteins were found to be related to microtubule-associated protein tau (MAPT) and amyloid-beta precursor protein (APP). RIIGL peptide acts on differentiated SH-SY5Y by regulating amyloid-beta formation, neuron apoptotic process, ceramide catabolic process, and oxidative phosphorylation and thus has the potentials to treat AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology/drug therapy
*Amyloid beta-Peptides/metabolism/pharmacology
*Neuroblastoma/pathology/metabolism/drug therapy
Cell Line, Tumor
*Cell Differentiation/drug effects
*Brain-Derived Neurotrophic Factor/metabolism/pharmacology
*tau Proteins/metabolism
Tretinoin/pharmacology
Amyloid beta-Protein Precursor/metabolism/genetics

@article {pmid39035101,
year = {2024},
author = {Singh, A and Singh, D and Tiwari, N and Mittal, P and Siddiqui, MH and Mittal, N},
title = {Exploring the therapeutic potential of rosemary compounds against Alzheimer's disease through GC-MS and molecular docking analysis.},
journal = {In silico pharmacology},
volume = {12},
number = {2},
pages = {63},
pmid = {39035101},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is the leading cause of dementia in elderly individuals. Currently, there is no permanent treatment option available for this disorder, and the existing drug regimens are associated with limited effectiveness and side effects. To evaluate the neuroprotective effect of rosemary compounds, an extensive study was started with gas chromatography-mass spectrometry (GC-MS) analysis. GC-MS was performed to study the composition of rosemary essential oil and a total of 120 volatile compounds were identified. The 36 compounds from GC-MS data of rosemary essential oil having > 1% concentration in the oil were selected along with 3 already reported well-known non-volatile compounds of rosemary. se39 bioactive natural compounds of rosemary were docked against ACE, BACE1, GSK3, and TACE proteins, which are involved in AD progression. The top 3 compounds against each target protein were selected based on their binding energies and a total of 6 compounds were found as best candidates to target the AD; α Amyrin, Rosmanol, Androsta-1,4-dien-3-one,16,17-dihydroxy-(16.beta.,17.beta), Benzenesulfonamide,4-methyl-N-(5-nitro-2-pyridinyl), Methyl abietate, and Rosmarinic acid were the best compounds. The binding energy of α-Amyrin, Rosmanol, and Androsta-1,4-dien-3-one,16,17-dihydroxy-(16.beta.,17.beta) to ACE target is -10 kcal/mol, -9.3 kcal/mol, and - 9.3 kcal/mol, respectively. The best binding affinity was shown by complexes formed between GSK3-α-Amyrin (-9.1 kcal/mol), BACE1- α-Amyrin (-9.9 kcal/mol), and TACE- Benzenesulfonamide,4-methyl-N-(5-nitro-2-pyridinyl) (-9.1 kcal/mol). The comparative analysis between known inhibitors/ drugs of target proteins and the rosemary compound that shows the highest binding affinity against each protein also revealed the higher potential of rosemary natural compounds in terms of binding energy. The drug-likeliness properties like Lipinski's rule of five and the ADME/T analysis of top-selected compounds were screened through PkCSM and Deep-PK tools. The findings from this study suggested that rosemary compounds have the potential as a therapeutic lead for treating AD. This kind of experimental confirmation can lead to novel drug candidates against the pharmacological targets of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-024-00238-9.},
}

@article {pmid39034660,
year = {2024},
author = {Iwata, A},
title = {How will the emergence of lecanemab change dementia treatment?.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.14945},
pmid = {39034660},
issn = {1447-0594},
abstract = {The introduction of lecanemab has dramatically changed the field of dementia medicine. Lecanemab, defined as an anti-amyloid-β (Aβ) drug, comprises an antibody against Aβ, a protein structure believed to cause Alzheimer's disease. This drug represents a new direction in dementia treatment. In a phase III study, lecanemab was found to significantly slow cognitive decline, while showing manageable levels of amyloid-related imaging abnormalities, which are side-effects of lecanemab. Furthermore, lecanemab has been shown to effectively reduce Aβ accumulation in patients with early Alzheimer's disease, which might contribute not only to delaying the progression of cognitive decline, but also to improving the quality of life of patients and their families. However, there are conditions for the use of lecanemab, for which the Ministry of Health, Labor and Welfare has issued the Guidelines for Promotion of Optimal Use. These guidelines specify requirements for appropriate patient selection, prescribing physicians and administering medical institutions to ensure safe and effective use. Particular emphasis is placed on the confirmation of amyloid-β accumulation, amyloid-related imaging abnormalities risk management and appropriate handling of side-effects. The clinical use of lecanemab represents an important advancement in the treatment of dementia; however, the understanding and cooperation of healthcare professionals, patients and families are essential to maximize its efficacy and safety. Future issues to be addressed include the sustainability and long-term efficacy of treatment, improvement of clinical symptoms after removal of Aβ and motivation to administer the drug. Although lecanemab offers hope for the treatment of dementia, its use requires careful management. Geriatr Gerontol Int 2024; ••: ••-••.},
}

@article {pmid39034293,
year = {2024},
author = {Koçak Aslan, E and Sezer, A and Tüylü Küçükkılınç, T and Palaska, E},
title = {Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation.},
journal = {Archiv der Pharmazie},
volume = {},
number = {},
pages = {e2400406},
doi = {10.1002/ardp.202400406},
pmid = {39034293},
issn = {1521-4184},
support = {//Hacettepe Üniversitesi/ ; THD-2019-18352 and THD-2022-19710//Hacettepe University Scientific Research Fund/ ; },
abstract = {Butyrylcholinesterase (BChE) is considered a promising therapeutic target for treating Alzheimer's disease due to the increase in the levels and activity of BChE in the late stage of the disease. In this study, a series of novel 1,2,4-triazole derivatives bearing the naphthalene moiety linked to the benzothiazole, thiazole, and phenyl scaffolds via amid chain were designed and synthesized as potential and selective BChE inhibitors. The results of the inhibitory activity studies revealed that most of these compounds exhibited significant inhibitor potency on BChE. Compounds 35a (0.025 ± 0.01 μM) and 37a (0.035 ± 0.01 μM) displayed the most potent inhibitory activity, with excellent selectivity against BChE over acetylcholinesterase (SIBChE, 23,686 and 16,936, respectively) among the target compounds. The kinetics studies revealed that these compounds behaved with noncompetitive BChE inhibitors. Molecular docking studies indicated that 35a and 37a fit well into the active side of BChE. In addition, 35a and 37a also had the lowest cytotoxicity for human neuroblastoma cells (SH-SY5Y), potential antioxidant capacity, moderate inhibition potency on amyloid-β1-42 aggregation, and significant neuroprotective effect against SH-SY5Y cell injury induced by H2O2 and amyloid-β1-42. All results suggest that these compounds might be considered as promising new lead compounds in the drug discovery process for the treatment of late-stage Alzheimer's disease.},
}

@article {pmid39032806,
year = {2024},
author = {Bhatt, A and Bhardwaj, H and Shrivastava, P},
title = {Mesenchymal stem cell therapy for Alzheimer's disease: A novel therapeutic approach for neurodegenerative diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2024.07.019},
pmid = {39032806},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood-brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aβ and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective.},
}

@article {pmid39032765,
year = {2024},
author = {Ren, X and Wen, Y and Yuan, M and Li, C and Zhang, J and Li, S and Zhang, X and Wang, L and Wang, S},
title = {Cerebroprotein hydrolysate-I ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via the p53/SAT1/ALOX15 signalling pathway.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {176820},
doi = {10.1016/j.ejphar.2024.176820},
pmid = {39032765},
issn = {1879-0712},
abstract = {Ferroptosis, an iron-dependent lipid peroxidation-driven cell death pathway, has been linked to the development of Alzheimer's disease (AD). However, the role of ferroptosis in the pathogenesis of AD remains unclear. Cerebroprotein hydrolysate-I (CH-I) is a mixture of peptides with neurotrophic effects that improves cognitive deficits and reduces amyloid burden. The present study investigated the ferroptosis-induced signalling pathways and the neuroprotective effects of CH-I in the brains of AD transgenic mice. Seven-month-old male APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with intraperitoneal injections of CH-I and saline for 28 days. The Morris water maze test was used to assess cognitive function. CH-I significantly improved cognitive deficits and attenuated beta-amyloid (Aβ) aggregation and tau phosphorylation in the hippocampus of APP/PS1 mice. RNA sequencing revealed that multiple genes and pathways, including ferroptosis-related pathways, were involved in the neuroprotective effects of CH-I. The increased levels of lipid peroxidation, ferrous ions, reactive oxygen species (ROS) , and altered expression of ferroptosis-related genes (recombinant solute carrier family 7, member 11 (SLC7A11), spermidine/spermine N1-acetyltransferase 1 (SAT1) and glutathione peroxidase 4 (GPX4)) were significantly alleviated after CH-I treatment. Quantitative real-time PCR and western blotting were performed to investigate the expression of key ferroptosis-related genes and the p53/SAT1/ arachidonic acid 15-lipoxygenase (ALOX15) signalling pathway. The p53/SAT1/ALOX15 signalling pathway was found to be involved in mediating ferroptosis, and the activation of this pathway was significantly suppressed in AD by CH-I. CH-I demonstrated neuroprotective effects against AD by attenuating ferroptosis and the p53/SAT1/ALOX15 signalling pathway, thus providing new targets for AD treatment.},
}

@article {pmid39032487,
year = {2024},
author = {Soeda, Y and Yoshimura, H and Bannai, H and Koike, R and Shiiba, I and Takashima, A},
title = {Intracellular tau fragment droplets serve as seeds for tau fibrils.},
journal = {Structure (London, England : 1993)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.str.2024.06.018},
pmid = {39032487},
issn = {1878-4186},
abstract = {Intracellular tau aggregation requires a local protein concentration increase, referred to as "droplets". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer's disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.},
}

@article {pmid39032401,
year = {2024},
author = {Gonçalves, PB and Sodero, ACR and Cordeiro, Y},
title = {Natural products targeting amyloid-β oligomer neurotoxicity in Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {276},
number = {},
pages = {116684},
doi = {10.1016/j.ejmech.2024.116684},
pmid = {39032401},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) constitutes a major global health issue, characterized by progressive neurodegeneration and cognitive impairment, for which no curative treatment is currently available. Current therapeutic approaches are focused on symptom management, highlighting the critical need for disease-modifying therapy. The hallmark pathology of AD involves the aggregation and accumulation of amyloid-β (Aβ) peptides in the brain. Consequently, drug discovery efforts in recent decades have centered on the Aβ aggregation cascade, which includes the transition of monomeric Aβ peptides into toxic oligomers and, ultimately, mature fibrils. Historically, anti-Aβ strategies focused on the clearance of amyloid fibrils using monoclonal antibodies. However, substantial evidence has highlighted the critical role of Aβ oligomers (AβOs) in AD pathogenesis. Soluble AβOs are now recognized as more toxic than fibrils, directly contributing to synaptic impairment, neuronal damage, and the onset of AD. Targeting AβOs has emerged as a promising therapeutic approach to mitigate cognitive decline in AD. Natural products (NPs) have demonstrated promise against AβO neurotoxicity through various mechanisms, including preventing AβO formation, enhancing clearance mechanisms, or converting AβOs into non-toxic species. Understanding the mechanisms by which anti-AβO NPs operate is useful for developing disease-modifying treatments for AD. In this review, we explore the role of NPs in mitigating AβO neurotoxicity for AD drug discovery, summarizing key evidence from biophysical methods, cellular assays, and animal models. By discussing how NPs modulate AβO neurotoxicity across various experimental systems, we aim to provide valuable insights into novel therapeutic strategies targeting AβOs in AD.},
}

@article {pmid39032283,
year = {2024},
author = {Pang, QQ and Zang, CX and Li, T and Zeng, XC and Liu, LX and Zhang, D and Yao, XS and Yu, Y},
title = {Neuroprotective effect of GJ-4 against cognitive impairments in vascular dementia by improving white matter damage.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {132},
number = {},
pages = {155877},
doi = {10.1016/j.phymed.2024.155877},
pmid = {39032283},
issn = {1618-095X},
abstract = {BACKGROUND: White matter lesions (WMLs) are increasingly linked to the pathological process of chronic vascular dementia (VaD). An effective crocins fraction extracted from Gardenia Fructus, GJ-4, has been shown to improve cognitive function in several Alzheimer's disease models and VaD models.

OBJECTIVES: To explore the potential mechanisms of GJ-4 on WMLs in a chronic VaD mouse model.

METHODS: The chronic VaD mouse model was established, and WMLs were characterized by cerebral blood flow (CBF), behavioral tests, LFB staining, and immunohistochemistry. The anti-oxidative effect of GJ-4 was validated by examining biochemical parameters (SOD, MDA, and GSH) and the Keap1-Nrf2/HO-1 pathway. The impact of GJ-4 on lipid metabolism in WM was further investigated through lipidomic analysis.

RESULTS: GJ-4 significantly attenuated cognitive impairments and improved the CBF of BCAS (bilateral common carotid artery stenosis)-induced mice. Mechanism research showed that GJ-4 could enhance cognition by promoting the repair of WMLs by inhibiting oxidative stress. Furthermore, GJ-4 treatment significantly reduced chronic cerebral hypoperfusion (CCH)-induced WMLs via improving lipid metabolism disorder in the WM.

CONCLUSION: This research has provided valuable insights into the significance of WMLs in CCH-induced VaD and underscored the potential of GJ-4 as a therapeutic agent for improving cognitive function by targeting WMLs. These findings suggest that GJ-4 is a promising candidate for the treatment of VaD.},
}

@article {pmid39031716,
year = {2024},
author = {By, S and Kahl, A and Cogswell, PM},
title = {Alzheimer's Disease Clinical Trials: What Have We Learned From Magnetic Resonance Imaging.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.29462},
pmid = {39031716},
issn = {1522-2586},
abstract = {Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia worldwide with rising prevalence, incidence and mortality. Despite many decades of research, there remains an unmet need for disease-modifying treatment that can significantly alter the progression of disease. Recently, with United States Food and Drug Administration (FDA) drug approvals, there have been tremendous advances in this area, with agents demonstrating effects on cognition and biomarkers. Magnetic resonance imaging (MRI) plays an instrumental role in these trials. This review article aims to outline how MRI is used for screening eligibility, monitoring safety and measuring efficacy in clinical trials, leaning on the landscape of past and recent AD clinical trials that have used MRI as examples; further, insight on promising MRI biomarkers for future trials is provided. LEVEL OF EVIDENCE: 1. TECHNICAL EFFICACY: Stage 4.},
}

@article {pmid39031538,
year = {2024},
author = {Ya, J and Zhang, H and Qin, G and Huang, C and Zhao, C and Ren, J and Qu, X},
title = {A Biocompatible Hydrogen-Bonded Organic Framework (HOF) as Sonosensitizer and Artificial Enzyme for In-Depth Treatment of Alzheimer's Disease.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e2402342},
doi = {10.1002/adhm.202402342},
pmid = {39031538},
issn = {2192-2659},
support = {2019YFA0709202//National Key R&D Program of China/ ; 2021YFF1200700//National Key R&D Program of China/ ; 21820102009//Natural Science Foundation of China/ ; 22237006//Natural Science Foundation of China/ ; 22207102//Natural Science Foundation of China/ ; 2023DJ02//Jilin Innovation Project/ ; 20210101130JC//Jilin Province Science and Technology Development Plan Project/ ; },
abstract = {Current phototherapeutic approaches for Alzheimer's disease (AD) exhibit restricted clinical outcomes due to the limited physical penetration and comprised brain microenvironment of noninvasive nanomedicine. Herein, a hydrogen-bonded organic framework (HOF) based sonosensitizer is designed and synthesized. Mn-TCPP, a planar molecule where Mn[2+] ion is chelated in the core with a large p-conjugated system and 4 carboxylate acid groups, has been successfully used as building blocks to construct an ultrasound-sensitive HOF (USI-MHOF), which can go deep in the brain of AD animal models. The both in vitro and in vivo studies indicate that USI-MHOF can generate singlet oxygen ([1]O2) and oxidize β-amyloid (Aβ) to inhibit aggregation, consequently attenuating Aβ neurotoxicity. More intriguingly, USI-MHOF exhibits catalase (CAT)- and superoxide dismutase (SOD)-like activities, mitigating neuron oxidative stress and reprograming the brain microenvironment. For better crossing the blood-brain barrier (BBB), the peptide KLVFFAED (KD8) has been covalently grafted to USI-MHOF for improving BBB permeability and Aβ selectivity. Further, in vivo experiments demonstrate a significant reduction of the craniocerebral Aβ plaques and improvement of the cognition deficits in triple-transgenic AD (3×Tg-AD) mice models following deep-penetration ultrasound treatment. The work provides the first example of an ultrasound-responsive biocompatible HOF as non-invasive nanomedicine for in-depth treatment of AD.},
}

@article {pmid39030751,
year = {2024},
author = {Wang, G and Cutter, G and Oxtoby, NP and Shan, G and Wang, W and Mangal, B and Liao, Y and Llibre-Guerra, JJ and Li, Y and Xiong, C and McDade, E and Delmar, P and Bateman, RJ and Schneider, L},
title = {Statistical considerations when estimating time-saving treatment effects in Alzheimer's disease clinical trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14035},
pmid = {39030751},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; U01AG042791/NH/NIH HHS/United States ; U01AG042791-S1/NH/NIH HHS/United States ; //FNIH/ ; R01AG046179//Accelerating Medicines Partnership/ ; R01AG053267-S1//Accelerating Medicines Partnership/ ; /AG/NIA NIH HHS/United States ; U01AG042791/NH/NIH HHS/United States ; U01AG042791-S1/NH/NIH HHS/United States ; },
abstract = {INTRODUCTION: Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods.

METHODS: We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial.

RESULTS: Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm.

DISCUSSION: Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods.

HIGHLIGHTS: We explore the statistical considerations of the current method for estimating time savings. We proposed alternative methods that provide time savings estimations based on the observed absolute differences. By using various methods, a more comprehensive estimation of time savings can be achieved.},
}

@article {pmid39030577,
year = {2024},
author = {Zhang, J and Jiang, Y and Dong, X and Meng, Z and Ji, L and Kang, Y and Liu, M and Zhou, W and Song, W},
title = {Alpha-lipoic acid alleviates cognitive deficits in transgenic APP23/PS45 mice through a mitophagy-mediated increase in ADAM10 α-secretase cleavage of APP.},
journal = {Alzheimer's research & therapy},
volume = {16},
number = {1},
pages = {160},
pmid = {39030577},
issn = {1758-9193},
mesh = {Animals ; *Thioctic Acid/pharmacology ; *Mice, Transgenic ; *Mitophagy/drug effects ; *ADAM10 Protein/metabolism ; Mice ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; Alzheimer Disease/drug therapy/metabolism/genetics ; Disease Models, Animal ; Membrane Proteins/metabolism/genetics ; Neuroprotective Agents/pharmacology ; Mice, Inbred C57BL ; Male ; },
abstract = {BACKGROUND: Alpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer's disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-β precursor protein (APP) metabolism has not been fully elucidated.

OBJECTIVE: To investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect.

METHODS: ALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP).

RESULTS: Administration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP.

CONCLUSIONS: The enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.},
}

Animals
*Thioctic Acid/pharmacology
*Mice, Transgenic
*Mitophagy/drug effects
*ADAM10 Protein/metabolism
Mice
*Amyloid beta-Protein Precursor/genetics/metabolism
*Cognitive Dysfunction/drug therapy/metabolism
*Amyloid Precursor Protein Secretases/metabolism
Alzheimer Disease/drug therapy/metabolism/genetics
Disease Models, Animal
Membrane Proteins/metabolism/genetics
Neuroprotective Agents/pharmacology
Mice, Inbred C57BL
Male

@article {pmid39029976,
year = {2024},
author = {Weber, CM and Moiz, B and Clyne, AM},
title = {Brain microvascular endothelial cell metabolism and its ties to barrier function.},
journal = {Vitamins and hormones},
volume = {126},
number = {},
pages = {25-75},
doi = {10.1016/bs.vh.2024.05.002},
pmid = {39029976},
issn = {0083-6729},
mesh = {Animals ; Humans ; *Blood-Brain Barrier/metabolism ; *Brain/metabolism ; *Endothelial Cells/metabolism ; Microvessels/metabolism ; Neurodegenerative Diseases/metabolism ; },
abstract = {Brain microvascular endothelial cells, which lie at the interface between blood and brain, are critical to brain energetics. These cells must precisely balance metabolizing nutrients for their own demands with transporting nutrients into the brain to sustain parenchymal cells. It is essential to understand this integrated metabolism and transport so that we can develop better diagnostics and therapeutics for neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, and traumatic brain injury. In this chapter, we first describe brain microvascular endothelial cell metabolism and how these cells regulate both blood flow and nutrient transport. We then explain the impact of brain microvascular endothelial cell metabolism on the integrity of the blood-brain barrier, as well as how metabolites produced by the endothelial cells impact other brain cells. We detail some ways that cell metabolism is typically measured experimentally and modeled computationally. Finally, we describe changes in brain microvascular endothelial cell metabolism in aging and neurodegenerative diseases. At the end of the chapter, we highlight areas for future research in brain microvascular endothelial cell metabolism. The goal of this chapter is to underscore the importance of nutrient metabolism and transport at the brain endothelium for cerebral health and neurovascular disease treatment.},
}

Animals
Humans
*Blood-Brain Barrier/metabolism
*Brain/metabolism
*Endothelial Cells/metabolism
Microvessels/metabolism
Neurodegenerative Diseases/metabolism

@article {pmid39029320,
year = {2024},
author = {Soltan, OM and Abdelrahman, KS and Bass, AKA and Takizawa, K and Narumi, A and Konno, H},
title = {Design of Multi-Target drugs of HDACs and other Anti-Alzheimer related Targets: Current strategies and future prospects in Alzheimer's diseases therapy.},
journal = {Bioorganic chemistry},
volume = {151},
number = {},
pages = {107651},
doi = {10.1016/j.bioorg.2024.107651},
pmid = {39029320},
issn = {1090-2120},
abstract = {Alzheimer disease (AD) is the most prevalent form of dementia that develops spontaneously in the elderly. It's worth mentioning that as people age, the epigenetic profile of the central nervous system cells changes, which may speed up the development of various neurodegenerative disorders including AD. Histone deacetylases (HDACs) are a class of epigenetic enzymes that can control gene expression without altering the gene sequence. Moreover, a promising strategy for multi-target hybrid design was proposed to potentially improve drug efficacy and reduce side effects. These hybrids are monocular drugs that contain various pharmacophore components and have the ability to bind to different targets at the same time. The HDACs ability to synergistically boost the performance of other anti-AD drugs, as well as the ease with which HDACs inhibitor cap group, can be modified. This has prompted numerous medicinal chemists to design a novel generation of HDACs multi-target inhibitors. Different HDACs inhibitors and other ones such as acetylcholinesterase, butyryl-cholinesterase, phosphodiesterase 9, phosphodiesterase 5 or glycogen synthase kinase 3β inhibitors were merged into hybrids for treatment of AD. This review goes over the scientific rationale for targeting HDACs along with several other crucial targets in AD therapy. This review presents the latest hybrids of HDACs and other AD target pharmacophores.},
}

@article {pmid39028199,
year = {2024},
author = {Dou, J and Zhang, H and Fu, X and Yang, Y and Gao, X},
title = {Optimal dose and type of non-pharmacological treatments to improve cognitive function in people with Alzheimer's disease: a systematic review and network meta-analysis.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/13607863.2024.2379427},
pmid = {39028199},
issn = {1364-6915},
abstract = {OBJECTIVES: To evaluate and rank the effectiveness of specific non-pharmacological treatments (NPTs) in improving the global cognitive function in individuals with Alzheimer's disease (AD) and to examine the dose-response relationship.

METHOD: We conducted a systematic search in PubMed, MEDLINE, Embase, PsycINFO, CENTRAL, WOS, and CNKI from their inception to 15 February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models.

RESULTS: We included 68 studies involving 5053 participants in this meta-analysis. The treatments with the highest cumulative probabilities for improving global cognitive function were transcranial direct current stimulation (tDCS), followed by physical exercise (PE), and repetitive transcranial magnetic stimulation (rTMS). Additionally, cognitive stimulation (CS), cognitive training CT), multidisciplinary program (MD), and reminiscence treatment (RT) also significantly improve the global cognitive function of people with AD. A non-linear dose-response association was observed for tDCS, PE, rTMS, CS, and CT with global cognitive improvement. Notably, no minimal threshold was identified for the beneficial effects of PE on cognition. The estimated minimal doses for clinically relevant changes in cognition were 33 min per week for tDCS, 330 MET-min per week for PE, and 8000 pulses per week for rTMS.

CONCLUSION: tDCS, PE, and rTMS are the better effective NPTs for enhancing global cognitive function in individuals with AD. Properly dosing these treatments can yield significant clinical benefits. Our findings support the clinical utility of low-dose exercise in improving cognition in people with AD.},
}

@article {pmid39027984,
year = {2024},
author = {Zoltowska, KM and Das, U and Lismont, S and Enzlein, T and Maesako, M and Houser, MCQ and Franco, ML and Özcan, B and Gomes Moreira, D and Karachentsev, D and Becker, A and Hopf, C and Vilar, M and Berezovska, O and Mobley, W and Chávez-Gutiérrez, L},
title = {Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
pmid = {39027984},
issn = {2050-084X},
support = {G0B2519N//Research Foundation Flanders/ ; R01 AG055523/AG/NIA NIH HHS/United States ; P01 AG015379/AG/NIA NIH HHS/United States ; RF1 AG044486/AG/NIA NIH HHS/United States ; R01AG055523/NH/NIH HHS/United States ; AG015379/NH/NIH HHS/United States ; R01 AG044486/AG/NIA NIH HHS/United States ; PID2021-127600NB-I00//Spanish Ministry of Science and Innovation/ ; AG044486/NH/NIH HHS/United States ; },
mesh = {*Amyloid Precursor Protein Secretases/metabolism ; *Amyloid beta-Peptides/metabolism ; Humans ; *Alzheimer Disease/metabolism ; *Signal Transduction ; Animals ; *Neurons/metabolism/drug effects ; Mice ; Feedback, Physiological ; Peptide Fragments/metabolism ; Cell Line ; },
abstract = {Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.},
}

*Amyloid Precursor Protein Secretases/metabolism
*Amyloid beta-Peptides/metabolism
Humans
*Alzheimer Disease/metabolism
*Signal Transduction
Animals
*Neurons/metabolism/drug effects
Mice
Feedback, Physiological
Peptide Fragments/metabolism
Cell Line

@article {pmid39027944,
year = {2024},
author = {Zou, DJ and Liu, RZ and Lv, YJ and Guo, JN and Fan, ML and Zhang, CJ and Xie, YY},
title = {Chromone-deferiprone hybrids as novel MAO-B inhibitors and iron chelators for the treatment of Alzheimer's disease.},
journal = {Organic & biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4ob00919c},
pmid = {39027944},
issn = {1477-0539},
abstract = {A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 μM and potent iron-chelating ability (pFe[3+] = 18.79) comparable to that of deferiprone (pFe[3+] = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.},
}

@article {pmid39027900,
year = {2024},
author = {O'Hare, N and Millican, K and Ebong, EE},
title = {Unraveling neurovascular mysteries: the role of endothelial glycocalyx dysfunction in Alzheimer's disease pathogenesis.},
journal = {Frontiers in physiology},
volume = {15},
number = {},
pages = {1394725},
pmid = {39027900},
issn = {1664-042X},
abstract = {While cardiovascular disease, cancer, and human immunodeficiency virus (HIV) mortality rates have decreased over the past 20 years, Alzheimer's Disease (AD) deaths have risen by 145% since 2010. Despite significant research efforts, effective AD treatments remain elusive due to a poorly defined etiology and difficulty in targeting events that occur too downstream of disease onset. In hopes of elucidating alternative treatment pathways, now, AD is commonly being more broadly defined not only as a neurological disorder but also as a progression of a variety of cerebrovascular pathologies highlighted by the breakdown of the blood-brain barrier. The endothelial glycocalyx (GCX), which is an essential regulator of vascular physiology, plays a crucial role in the function of the neurovascular system, acting as an essential vascular mechanotransducer to facilitate ultimate blood-brain homeostasis. Shedding of the cerebrovascular GCX could be an early indication of neurovascular dysfunction and may subsequently progress neurodegenerative diseases like AD. Recent advances in in vitro modeling, gene/protein silencing, and imaging techniques offer new avenues of scrutinizing the GCX's effects on AD-related neurovascular pathology. Initial studies indicate GCX degradation in AD and other neurodegenerative diseases and have begun to demonstrate a possible link to GCX loss and cerebrovascular dysfunction. This review will scrutinize the GCX's contribution to known vascular etiologies of AD and propose future work aimed at continuing to uncover the relationship between GCX dysfunction and eventual AD-associated neurological deterioration.},
}

@article {pmid39027235,
year = {2024},
author = {Barrera-Ocampo, A},
title = {Monoclonal antibodies and aptamers: The future therapeutics for Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {14},
number = {7},
pages = {2795-2814},
pmid = {39027235},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) is considered the most common and prevalent form of dementia of adult-onset with characteristic progressive impairment in cognition and memory. The cure for AD has not been found yet and the treatments available until recently were only symptomatic. Regardless of multidisciplinary approaches and efforts made by pharmaceutical companies, it was only in the past two years that new drugs were approved for the treatment of the disease. Amyloid beta (Aβ) immunotherapy is at the core of this therapy, which is one of the most innovative approaches looking to change the course of AD. This technology is based on synthetic peptides or monoclonal antibodies (mAb) to reduce Aβ levels in the brain and slow down the advance of neurodegeneration. Hence, this article reviews the state of the art about AD neuropathogenesis, the traditional pharmacologic treatment, as well as the modern active and passive immunization describing approved drugs, and drug prototypes currently under investigation in different clinical trials. In addition, future perspectives on immunotherapeutic strategies for AD and the rise of the aptamer technology as a non-immunogenic alternative to curb the disease progression are discussed.},
}

@article {pmid39027123,
year = {2024},
author = {Кондаурова, ЕМ and Komarova, AA and Ilchibaeva, TV and Rodnyy, AY and Zalivina, EA and Naumenko, VS},
title = {Effect of amisulpride on the expression of serotonin receptors, neurotrophic factor BDNF and its receptors in mice with overexpression of the aggregation-prone [R406W] mutant tau protein.},
journal = {Vavilovskii zhurnal genetiki i selektsii},
volume = {28},
number = {4},
pages = {398-406},
doi = {10.18699/vjgb-24-45},
pmid = {39027123},
issn = {2500-0462},
abstract = {Serotonin 5-HT7 receptors (5-HT7R) are attracting increasing attention as important participants in the mechanisms of Alzheimer's disease and as a possible target for the treatment of various tau pathologies. In this study, we investigated the effects of amisulpride (5-HT7R inverse agonist) in C57BL/6J mice with experimentally induced expression of the gene encoding the aggregation-prone human Tau[R406W] protein in the prefrontal cortex. In these animals we examined short-term memory and the expression of genes involved in the development of tauopathy (Htr7 and Cdk5), as well as biomarkers of neurodegenerative processes - the Bdnf gene and its receptors TrkB (the Ntrk2 gene) and p75NTR (the Ngfr gene). In a short-term memory test, there was no difference in the discrimination index between mice treated with AAV-Tau[R406W] and mice treated with AAV-EGFP. Amisulpride did not affect this parameter. Administration of AAV-Tau[R406W] resulted in increased expression of the Htr7, Htr1a, and Cdk5 genes in the prefrontal cortex compared to AAV-EGFP animals. At the same time, amisulpride at the dose of 10 mg/kg in animals from the AAV-Tau[R406W] group caused a decrease in the Htr7, Htr1a genes mRNA levels compared to animals from the AAV-Tau[R406W] group treated with saline. A decrease in the expression of the Bdnf and Ntrk2 genes in the prefrontal cortex was revealed after administration of AAV-Tau[R406W]. Moreover, amisulpride at various doses (3 and 10 mg/kg) caused the same decrease in the transcription of these genes in mice without tauopathy. It is also interesting that in mice of the AAV-EGFP group, administration of amisulpride at the dose of 10 mg/kg increased the Ngfr gene mRNA level. The data obtained allow us to propose the use of amisulpride in restoring normal tau protein function. However, it should be noted that prolonged administration may result in adverse effects such as an increase in Ngfr expression and a decrease in Bdnf and Ntrk2 expression, which is probably indicative of an increase in neurodegenerative processes.},
}

@article {pmid39026868,
year = {2024},
author = {Isei, MO and Crockett, M and Chen, E and Rodwell-Bullock, J and Caroll, T and Girardi, PA and Nehrke, K and Johnson, GV},
title = {Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39026868},
issn = {2692-8205},
support = {R01 AG067617/AG/NIA NIH HHS/United States ; },
abstract = {Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimer's-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in C. elegans. Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimer's disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.},
}

@article {pmid39025434,
year = {2024},
author = {Baghaee, P and Yoonesi, M and Esfahani, DE and Beirami, E and Dargahi, L and Rashidi, FS and Valian, N},
title = {Yttrium oxide nanoparticles alleviate cognitive deficits, neuroinflammation, and mitochondrial biogenesis impairment induced by streptozotocin.},
journal = {Neuroscience letters},
volume = {837},
number = {},
pages = {137895},
doi = {10.1016/j.neulet.2024.137895},
pmid = {39025434},
issn = {1872-7972},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Yttrium oxide nanoparticles (Y2O3NPs) have recently attracted much attention for their potential anti-inflammatory and antioxidant properties. However, the effects of Y2O3NPs in animal models of AD are less studied. This study aimed to investigate the potential therapeutic effects of Y2O3NPs in streptozotocin (STZ)-treated rats, a reliable animal model of AD, with special emphasis on cognitive function, neuroinflammation, and mitochondrial biogenesis in the hippocampus. Male Wistar rats were stereotaxically injected with STZ (3 mg/kg, 3 µl/ventricle). Three weeks after STZ injection, cognitive function was assessed using the Morris water maze, elevated plus maze, and passive avoidance tasks. Intraperitoneal treatment with Y2O3NPs (0.1, 0.3, or 0.5 mg/kg) was started 24 h after the STZ injection and continued for 21 days. The mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and components involved in mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM) were measured in the hippocampus. The results indicated that STZ induced cognitive impairment and led to neuroinflammation and mitochondrial biogenesis impairment in the hippocampus of rats. Interestingly, treatment with Y2O3NPs effectively reduced STZ-induced cognitive deficits in a dose-dependent manner, possibly by attenuating neuroinflammation and mitochondrial biogenesis impairment. These findings suggest that Y2O3NPs can be considered as a promising therapeutic agent for treating or ameliorating the neuropathological effects associated with AD.},
}

@article {pmid39024573,
year = {2024},
author = {Nagy, LV and Bali, ZK and Ledneczki, I and Némethy, Z and Lendvai, B and Hernádi, I},
title = {Cellular Mechanisms of Cognitive Enhancement: The In Vivo Modulation of the Firing Activity and the Responsiveness of Rat Hippocampal Neurons by Memantine and Alpha7 Nicotinic Acetylcholine Receptor Ligands.},
journal = {ASN neuro},
volume = {16},
number = {1},
pages = {2371160},
doi = {10.1080/17590914.2024.2371160},
pmid = {39024573},
issn = {1759-0914},
mesh = {Animals ; *Memantine/pharmacology ; *alpha7 Nicotinic Acetylcholine Receptor/metabolism/agonists/antagonists & inhibitors ; *Hippocampus/drug effects ; Male ; Rats ; Neurons/drug effects/physiology ; Action Potentials/drug effects/physiology ; Dose-Response Relationship, Drug ; Cognition/drug effects/physiology ; Excitatory Amino Acid Antagonists/pharmacology ; Nootropic Agents/pharmacology ; Rats, Wistar ; Ligands ; Nicotinic Agonists/pharmacology ; },
abstract = {Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the in vivo firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer's disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.},
}

Animals
*Memantine/pharmacology
*alpha7 Nicotinic Acetylcholine Receptor/metabolism/agonists/antagonists & inhibitors
*Hippocampus/drug effects
Male
Rats
Neurons/drug effects/physiology
Action Potentials/drug effects/physiology
Dose-Response Relationship, Drug
Cognition/drug effects/physiology
Excitatory Amino Acid Antagonists/pharmacology
Nootropic Agents/pharmacology
Rats, Wistar
Ligands
Nicotinic Agonists/pharmacology

@article {pmid39024352,
year = {2024},
author = {Kelemen, L and Gupta, I and Yavarow, Z and Smith, SI and Johnson, KG and Boucher, NA},
title = {Clinician's perspectives on gene therapy for Alzheimer's disease: A qualitative study.},
journal = {PloS one},
volume = {19},
number = {7},
pages = {e0307567},
pmid = {39024352},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/therapy/genetics/psychology ; *Genetic Therapy/methods ; Male ; *Qualitative Research ; Female ; Quality of Life ; Middle Aged ; Decision Making ; Health Knowledge, Attitudes, Practice ; Adult ; Attitude of Health Personnel ; },
abstract = {INTRODUCTION: We aimed to understand clinician views regarding gene therapy as a future treatment for Alzheimer's disease (AD) and potential barriers and facilitators to its use.

METHODS: We interviewed ten clinicians who treat patients with AD. Clinicians helped design a semi-structured interview including the following domains: establishing understanding, cost/access, quality of life, and religion/spirituality. Transcripts were analyzed by a coding team using descriptive content analysis with inductive approach.

RESULTS: Clinicians identified three main areas of concern: 1) potential clinician and patient understanding of gene therapy and Alzheimer's disease 2) consideration of inequity (i.e., care access, disease awareness along with education level, family support, trust in care systems); and 3) considerations in decision-making (i.e., religious/spiritual beliefs and method of treatment delivery as a decision-making tools).

DISCUSSION AND CONCLUSION: Findings highlight areas for knowledge-building for patients and clinicians alike. Clinicians must be aware of patient/family educational needs and gaps in their own clinical knowledge before engaging patients/families with new technology. Allowing time for questions is crucial to building rapport and trust.},
}

Humans
*Alzheimer Disease/therapy/genetics/psychology
*Genetic Therapy/methods
Male
*Qualitative Research
Female
Quality of Life
Middle Aged
Decision Making
Health Knowledge, Attitudes, Practice
Adult
Attitude of Health Personnel

@article {pmid39023661,
year = {2024},
author = {Hussain, MA and Qaisar, R and Karim, A and Ahmad, F and Franzese, F and Awad, A and Al-Masri, AA and Alsaeed, M and Alkahtani, SA},
title = {Predictors of hip fracture in 15 European countries: a longitudinal study of 48,533 geriatric adults using SHARE dataset.},
journal = {Archives of osteoporosis},
volume = {19},
number = {1},
pages = {60},
pmid = {39023661},
issn = {1862-3514},
support = {RSP2024R277//King Saud University/ ; },
mesh = {Humans ; *Hip Fractures/epidemiology ; Female ; Male ; Aged ; Europe/epidemiology ; Risk Factors ; Middle Aged ; Longitudinal Studies ; Aged, 80 and over ; Hand Strength ; Depression/epidemiology ; Sex Factors ; Comorbidity ; },
abstract = {UNLABELLED: We investigated the risk factors for hip fracture in 48,533 European older adults for 8 years from 2013 onward. We identified female gender, age above 80, low handgrip strength, and depression as significant risk factors for hip fracture. Our findings may help identify high-risk populations for hip fractures in pre-clinical settings.

OBJECTIVES: Hip fracture is a major cause of functional disability, mortality, and health costs. However, the identification and characterization of its causative factors remain poor.

METHODS: We investigated demography, handgrip strength (HGS), depression, and multiple age-associated comorbidities for predicting future hip fracture in individuals aged 50 or above from 15 European countries (n = 48,533). All participants were evaluated from 2013 to 2020 using four successive waves of the Survey of Health, Aging, and Retirement in Europe (SHARE).

RESULTS: Altogether, 1130 participants developed hip fractures during the study period. We identified female gender, an advancing age from quinquagenarians onward, and a poor socioeconomic status as critical risk factors for future hip fracture. Having mobility difficulty, a low HGS (< 27 kg in men, < 16 kg in women) and higher scores on Euro-D depression scales were also significant risk factors for hip fracture. Summated scales of hypertension, diabetes mellitus, cancer, Alzheimer's disease, and stroke did not appear as risk factors.

CONCLUSION: Collectively, we report advancing age, female gender, low HGS, and depression as independent risk factors for hip fracture. Our findings are useful in identifying high-risk populations for hip fractures in pre-clinical settings before rigorous evaluation and treatment in clinics.},
}

Humans
*Hip Fractures/epidemiology
Female
Male
Aged
Europe/epidemiology
Risk Factors
Middle Aged
Longitudinal Studies
Aged, 80 and over
Hand Strength
Depression/epidemiology
Sex Factors
Comorbidity

@article {pmid39022909,
year = {2024},
author = {Zlobin, A and Smirnov, I and Golovin, A},
title = {Dynamic interchange between two protonation states is characteristic of active sites of cholinesterases.},
journal = {Protein science : a publication of the Protein Society},
volume = {33},
number = {8},
pages = {e5100},
pmid = {39022909},
issn = {1469-896X},
support = {21-74-20113//Russian Science Foundation/ ; },
mesh = {*Catalytic Domain ; *Protons ; *Molecular Dynamics Simulation ; *Butyrylcholinesterase/chemistry/metabolism ; Humans ; Hydrogen Bonding ; Acetylcholinesterase/chemistry/metabolism ; Cholinesterases/chemistry/metabolism ; },
abstract = {Cholinesterases are well-known and widely studied enzymes crucial to human health and involved in neurology, Alzheimer's, and lipid metabolism. The protonation pattern of active sites of cholinesterases influences all the chemical processes within, including reaction, covalent inhibition by nerve agents, and reactivation. Despite its significance, our comprehension of the fine structure of cholinesterases remains limited. In this study, we employed enhanced-sampling quantum-mechanical/molecular-mechanical calculations to show that cholinesterases predominantly operate as dynamic mixtures of two protonation states. The proton transfer between two non-catalytic glutamate residues follows the Grotthuss mechanism facilitated by a mediator water molecule. We show that this uncovered complexity of active sites presents a challenge for classical molecular dynamics simulations and calls for special treatment. The calculated proton transfer barrier of 1.65 kcal/mol initiates a discussion on the potential existence of two coupled low-barrier hydrogen bonds in the inhibited form of butyrylcholinesterase. These findings expand our understanding of structural features expressed by highly evolved enzymes and guide future advances in cholinesterase-related protein and drug design studies.},
}

*Catalytic Domain
*Protons
*Molecular Dynamics Simulation
*Butyrylcholinesterase/chemistry/metabolism
Humans
Hydrogen Bonding
Acetylcholinesterase/chemistry/metabolism
Cholinesterases/chemistry/metabolism

@article {pmid39022884,
year = {2024},
author = {Qiu, Z and Deng, X and Fu, Y and Jiang, M and Cui, X},
title = {Exploring the triad: VPS35, neurogenesis, and neurodegenerative diseases.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.16184},
pmid = {39022884},
issn = {1471-4159},
support = {NO. 82201574//National Natural Science Foundation of China/ ; NO. 2021A1515110573//the Guangdong Basic and Applied Basic Research Foundation/ ; NO.2023D01A61//General Program of Natural Science Foundation of Xinjiang Uygur Autonomous Region/ ; },
abstract = {Vacuolar protein sorting 35 (VPS35), a critical component of the retromer complex, plays a pivotal role in the pathogenesis of neurodegenerative diseases (NDs). It is involved in protein transmembrane sorting, facilitating the transport from endosomes to the trans-Golgi network (TGN) and plasma membrane. Recent investigations have compellingly associated mutations in the VPS35 gene with neurodegenerative disorders such as Parkinson's and Alzheimer's disease. These genetic alterations are implicated in protein misfolding, disrupted autophagic processes, mitochondrial dysregulation, and synaptic impairment. Furthermore, VPS35 exerts a notable impact on neurogenesis by influencing neuronal functionality, protein conveyance, and synaptic performance. Dysregulation or mutation of VPS35 may escalate the progression of neurodegenerative conditions, underscoring its pivotal role in safeguarding neuronal integrity. This review comprehensively discusses the role of VPS35 and its functional impairments in NDs. Furthermore, we provide an overview of the impact of VPS35 on neurogenesis and further explore the intricate relationship between neurogenesis and NDs. These research advancements offer novel perspectives and valuable insights for identifying potential therapeutic targets in the treatment of NDs.},
}

@article {pmid39021510,
year = {2024},
author = {Corriveau-Lecavalier, N and Botha, H and Graff-Radford, J and Switzer, AR and Przybelski, SA and Wiste, HJ and Murray, ME and Reichard, RR and Dickson, DW and Nguyen, AT and Ramanan, VK and McCarter, SJ and Boeve, BF and Machulda, MM and Fields, JA and Stricker, NH and Nelson, PT and Grothe, MJ and Knopman, DS and Lowe, VJ and Petersen, RC and Jack, CR and Jones, DT},
title = {Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome.},
journal = {Brain communications},
volume = {6},
number = {4},
pages = {fcae183},
pmid = {39021510},
issn = {2632-1297},
abstract = {Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.},
}

@article {pmid39021181,
year = {2024},
author = {Kushwah, S and Mani, A},
title = {Comprehensive Investigation of Natural Ligands as Inhibitors of β Secretase to Identify Alzheimer's Disease Therapeutics.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050323622240705043337},
pmid = {39021181},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is an alarmingly prevalent worldwide neurological disorder that affects millions of people and has severe effects on cognitive functions. The amyloid hypothesis, which links AD to Aβ (amyloid beta) plaque aggregation, is a well-acknowledged theory. The β-secretase (BACE1) is the main cause of Aβ production, which makes it a possible target for therapy. FDA-approved therapies for AD do exist, but none of them explicitly target BACE1, and their effectiveness is constrained and accompanied by adverse effects.

MATERIALS AND METHODS: We determined the essential chemical components of medicinal herbs by conducting a thorough literature research for BACE1. Computational methods like molecular docking, ADMET (Absorption, distribution, metabolism, excretion, toxicity) screening, molecular dynamic simulations, and MMPBSA analysis were performed in order to identify the most promising ligands for β-secretase.

RESULTS: The results suggested that withasomniferol, tinosporide, and curcumin had better binding affinity with BACE1, suggesting their potential as therapeutic candidates against Alzheimer's disease.

CONCLUSION: Herbal therapeutics have immense applications in the treatment of chronic diseases like Alzheimer's disease, and there is an urgent need to assess their efficacy as therapeutics.},
}

@article {pmid39021081,
year = {2024},
author = {Guo, RW and Xie, WJ and Yu, B and Song, C and Ji, XM and Wang, XY and Zhang, M and Zhang, X},
title = {Rotating magnetic field inhibits Aβ protein aggregation and alleviates cognitive impairment in Alzheimer's disease mice.},
journal = {Zoological research},
volume = {45},
number = {4},
pages = {924-936},
doi = {10.24272/j.issn.2095-8137.2024.034},
pmid = {39021081},
issn = {2095-8137},
mesh = {Animals ; *Alzheimer Disease/metabolism/therapy ; Mice ; *Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction ; Mice, Transgenic ; Magnetic Fields ; Disease Models, Animal ; Plaque, Amyloid ; Brain/metabolism ; },
abstract = {Amyloid beta (Aβ) monomers aggregate to form fibrils and amyloid plaques, which are critical mechanisms in the pathogenesis of Alzheimer's disease (AD). Given the important role of Aβ1-42 aggregation in plaque formation, leading to brain lesions and cognitive impairment, numerous studies have aimed to reduce Aβ aggregation and slow AD progression. The diphenylalanine (FF) sequence is critical for amyloid aggregation, and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings. In this study, we examined the effects of a moderate-intensity rotating magnetic field (RMF) on Aβ aggregation and AD pathogenesis. Results indicated that the RMF directly inhibited Aβ amyloid fibril formation and reduced Aβ-induced cytotoxicity in neural cells in vitro. Using the AD mouse model APP/PS1, RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments, including exploration and spatial and non-spatial memory abilities. Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation, attenuated microglial activation, and reduced oxidative stress in the APP/PS1 mouse brain. These findings suggest that RMF holds considerable potential as a non-invasive, high-penetration physical approach for AD treatment.},
}

Animals
*Alzheimer Disease/metabolism/therapy
Mice
*Amyloid beta-Peptides/metabolism
*Cognitive Dysfunction
Mice, Transgenic
Magnetic Fields
Disease Models, Animal
Plaque, Amyloid
Brain/metabolism

@article {pmid39021051,
year = {2024},
author = {Phanrang, PT and Upadhyaya, J and Chandra, AK and Sarmah, A and Hobza, P and Aguan, K and Mitra, S},
title = {Bio-Nano Synergy in Therapeutic Applications: Drug-Graphene Oxide Nanocomposites for Modulated Acetylcholinesterase Inhibition and Radical Scavenging.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.4c03351},
pmid = {39021051},
issn = {1520-5207},
abstract = {The current study explores the synergistic application of biophysical chemistry and nanotechnology in therapeutic treatments, focusing specifically on the development of advanced biomaterials to repurpose FDA-approved Alzheimer's disease (AD) drugs as potent antioxidants. By integration of AD drugs into graphene oxide (GO) nanocomposites, an attempt to enhance the acetylcholinesterase (AChE) inhibition and increase radical scavenging activity is proposed. This bionano synergy is designed to leverage the unique properties of both the nanomaterial surface and the bioactive compounds, improving treatment effectiveness. The nanocomposites also promise targeted drug delivery, as GO can traverse the blood-brain barrier to inhibit AChE more effectively in AD patients. Furthermore, the drug-GO nanocomposite exhibits enhanced radical scavenging capabilities, offering additional therapeutic benefits. This study also elucidates a molecular level understanding on how the properties of the drugs are modified when integrated into nanocomposites with GO, enabling the development of more effective materials. The interdisciplinary approach presented in this study exploits the potential of nanotechnology to enhance drug delivery systems and achieve superior therapeutic outcomes through bionano synergy.},
}

@article {pmid39020526,
year = {2024},
author = {Poblano, J and Castillo-Tobías, I and Berlanga, L and Tamayo-Ordoñez, MC and Del Carmen Rodríguez-Salazar, M and Silva-Belmares, SY and Aguayo-Morales, H and Cobos-Puc, LE},
title = {Drugs targeting APOE4 that regulate beta-amyloid aggregation in the brain: Therapeutic potential for Alzheimer's disease.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bcpt.14055},
pmid = {39020526},
issn = {1742-7843},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, and behavioural and psychological symptoms of dementia are common. The APOE ε4 allele, a genetic risk factor, significantly increases susceptibility to the disease. Despite efforts to effectively treat the disease, only seven drugs are approved for its treatment, and only two of these prevent its progression. This highlights the need to identify new pharmacological options. This review focuses on mimetic peptides, small molecule correctors and HAE-4 antibodies that target ApoE. These drugs reduce β-amyloid-induced neurodegeneration in preclinical models. In addition, loop diuretics such as bumetanide and furosemide show the potential to reduce the prevalence of Alzheimer's disease in humans, and antidepressants such as imipramine improve cognitive function in individuals diagnosed with Alzheimer's disease. Consistent with this, both classes of drugs have been shown to exert neuroprotective effects by inhibiting ApoE4-catalysed Aβ aggregation in preclinical models. Moreover, peroxisome proliferator-activated receptor ligands, particularly pioglitazone and rosiglitazone, reduce ApoE4-induced neurodegeneration in animal models. However, they do not prevent the cognitive decline in APOE ε4 allele carriers. Finally, ApoE4 impairs the integrity of the blood-brain barrier and haemostasis. On this basis, ApoE4 modulation is a promising avenue for the treatment of late-onset Alzheimer's disease.},
}

@article {pmid39019369,
year = {2024},
author = {Liu, YC and Chen, SY and Chen, YY and Chang, HY and Chiang, IC and Yen, GC},
title = {Polysaccharides extracted from common buckwheat (Fagopyrum esculentum) attenuate cognitive impairment via suppressing RAGE/p38/NF-κB signaling and dysbiosis in AlCl3-treated rats.},
journal = {International journal of biological macromolecules},
volume = {276},
number = {Pt 2},
pages = {133898},
doi = {10.1016/j.ijbiomac.2024.133898},
pmid = {39019369},
issn = {1879-0003},
abstract = {Patients may find it challenging to accept several FDA-approved drugs for Alzheimer's disease (AD) treatment due to their unaffordable prices and side effects. Despite the known antioxidant, anti-inflammatory, and microbiota-regulating effects of common buckwheat (Fagopyrum esculentum) polysaccharides (FEP), their specific role in preventing AD has not been determined. Here, this study investigated the preventive effects of FEP on AD development in AlCl3-treated rats. The physical properties of FEP were evaluated using X-ray diffraction, FTIR, TGA, DSC, monosaccharide composition, molecular weight, and scanning electron microscopy. The results demonstrated that FEP administration improved memory and learning ability in AlCl3-treated rats. Additionally, AD pathological biomarkers (APP, BACE1, Aβ1-42, and p-Tau[Ser404]), inflammatory-associated proteins (IL-1β, IL-6, TNF-α, and Iba1), and MDA and the RAGE/p38/NF-κB pathway were elevated in AlCl3-treated rats. Moreover, these effects were reversed by the upregulation of LRP1, anti-inflammatory cytokines (IL-4 and IL-10), antioxidant enzymes (SOD and catalase), and autophagy proteins (Atg5, Beclin-1, and LC3B). Furthermore, FEP treatment increased the levels of short-chain fatty acids (SCFAs) and the abundance of SCFAs-producing microbes ([Eubacterium]_xylanophilum_group, Lachnospiraceae_NK4A136_group, Lactobacillus). Overall, FEP mitigated oxidative stress, RAGE/p38/NF-κB-mediated neuroinflammation, and AD-associated proteins by upregulating autophagy and SCFA levels, which led to the amelioration of cognitive impairment through microbiota-gut-brain communication in AlCl3-treated rats.},
}

@article {pmid39019356,
year = {2024},
author = {Guan, Y and Wang, C and Li, L and Dai, X and Liu, Y and Hsiang, T and Liu, S and Wang, D},
title = {Structural characterization of Hericium coralloides polysaccharide and its neuroprotective function in Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {133865},
doi = {10.1016/j.ijbiomac.2024.133865},
pmid = {39019356},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder. Polysaccharides have been scientifically demonstrated to possess neuroprotective properties. In this study, a polysaccharide was isolated from the fruiting bodies of Hericium coralloides using hot water extraction and purified using column chromatography. This H. coralloides polysaccharide (HCP) is a galactan with a main chain of →6)-α-d-Galp-(1 → and a molecular weight of 16.06 kDa. The partial α-l-Fucp-(1 → substitution takes place at its O-2 position. The neuroprotective effects of HCP were investigated in an APP/PS1 mouse model of Alzheimer's disease. The step-down and Morris water maze tests demonstrated that HCP effectively ameliorated cognitive impairment. After 8-week treatment, HCP reduced amyloid-β plaques and phosphorylated tau protein deposition. In combination with the gut microbiota and metabolites, proteomic analysis suggested that the neuroprotective effects of HCP are associated with neuroinflammation and autophagy. Immunofluorescence and western blotting analyses confirmed that HCP facilitated the polarization of M2 microglia by augmenting autophagy flux, thereby effectively reducing levels of amyloid-β plaques and neuroinflammation. These data demonstrate that HCP effectively mitigates neuroinflammation by enhancing autophagic flux, demonstrating its potential for the treatment of AD.},
}

@article {pmid39019341,
year = {2024},
author = {El-Sayed, SS and Ali, SO and Ibrahim, WW},
title = {Potential neuroprotective and autophagy-enhancing effects of alogliptin on lithium/pilocarpine-induced seizures in rats: Targeting the AMPK/SIRT1/Nrf2 axis.},
journal = {Life sciences},
volume = {352},
number = {},
pages = {122917},
doi = {10.1016/j.lfs.2024.122917},
pmid = {39019341},
issn = {1879-0631},
abstract = {BACKGROUND: Status epilepticus (SE) as a severe neurodegenerative disease, greatly negatively affects people's health, and there is an urgent need for innovative treatments. The valuable neuroprotective effects of glucagon-like peptide-1 (GLP-1) in several neurodegenerative diseases have raised motivation to investigate the dipeptidyl peptidase-4 (DPP-4) inhibitor; alogliptin (ALO), an oral antidiabetic drug as a potential treatment for SE. ALO has shown promising neuroprotective effects in Alzheimer's and Parkinson's diseases, but its impact on SE has not yet been studied.

AIM: The present study aimed to explore the repurposing potential for ALO in a lithium/pilocarpine (Li/Pil)-induced SE model in rats.

MAIN METHODS: ALO (30 mg/kg/day) was administered via gavage for 14 days, and SE was subsequently induced in the rats using a single dose of Li/Pil (127/60 mg/kg), while levetiracetam was used as a standard antiepileptic drug.

KEY FINDINGS: The results showed that ALO reduced seizure severity and associated hippocampal neurodegeneration. ALO also increased γ-aminobutyric acid (GABA) levels, diminished glutamate spikes, and corrected glial fibrillary acidic protein (GFAP) changes. At the molecular level, ALO increased GLP-1 levels and activated its downstream signaling pathway, AMP-activated protein kinase (AMPK)/sirtuin-1 (SIRT1). ALO also dampened the brain's pro-oxidant response, curbed neuroinflammation, and counteracted hippocampal apoptosis affording neuroprotection. In addition, it activated autophagy as indicated by Beclin1 elevation.

SIGNIFICANCE: This study suggested that the neuroprotective properties and autophagy-enhancing effects of ALO make it a promising treatment for SE and can potentially be used as a management approach for this condition.},
}

@article {pmid39019196,
year = {2024},
author = {Lin, HY and Feng, YH and Kao, TJ and Chen, HC and Chen, GY and Ko, CY and Hsu, TI},
title = {Exploring Neuron-Specific Steroid Synthesis and DHEAS Therapy in Alzheimer's Disease.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {},
number = {},
pages = {106585},
doi = {10.1016/j.jsbmb.2024.106585},
pmid = {39019196},
issn = {1879-1220},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies have suggested a potential role for steroid synthesis in AD pathology. This study investigated the co-localization of steroidogenic enzymes in neuronal cells, changes in enzyme expression in an AD mouse model, and steroid expressions in human AD samples. Additionally, we conducted a steroidomic metabolomics analysis and evaluated the effects of dehydroepiandrosterone sulfate (DHEAS) treatment in an AD mouse model. Immunofluorescence analysis revealed significant co-localization of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and steroidogenic acute regulatory protein (StAR) proteins with α-synuclein in presynaptic neurons, suggesting active steroid synthesis in these cells. Conversely, such co-localization was absent in astrocytes. In the AD mouse model, a marked decrease in the expression of steroidogenic enzymes (Cyp11a1, Cyp17a1, Star) was observed, especially in areas with amyloid beta plaque accumulation. Human AD and MS brain tissues showed similar reductions in StAR and CYP17A1 expressions. Steroidomic analysis indicated a downregulation of key steroids in the serum of AD patients. DHEAS treatment in AD mice resulted in improved cognitive function and reduced Aβ accumulation. Our findings indicate a neuron-specific pathway for steroid synthesis, potentially playing a crucial role in AD pathology. The reduction in steroidogenic enzymes and key steroids in AD models and human samples suggests that impaired steroid synthesis is a feature of neurodegenerative diseases. The therapeutic potential of targeting steroid synthesis pathways, as indicated by the positive effects of DHEAS treatment, warrants further investigation.},
}

@article {pmid39018956,
year = {2024},
author = {Hasan, G},
title = {Septin regulation of Orai-mediated Ca[2+] entry - a novel target for neurodegeneration.},
journal = {Cell calcium},
volume = {123},
number = {},
pages = {102929},
doi = {10.1016/j.ceca.2024.102929},
pmid = {39018956},
issn = {1532-1991},
abstract = {Aberrant Ca[2+] signaling is an early hallmark of multiple neurodegenerative syndromes including Alzheimer's and Parkinson's disease (AD and PD) as well as classes of rare genetic disorders such as Spinocebellar Ataxias. Therapeutic strategies that target aberrant Ca[2+] signals whilst allowing normal neuronal Ca[2+] signals have been a challenge. In a recent study Princen et al., performed a screen in the tauP301L cell model of AD for drugs that could specifically ameliorate the excess Ca[2+] entry observed. They identified a class of compounds referred to as ReS19-T that interact with Septins, previously identified as regulators of the Store-operated Ca[2+] entry channel Orai. Drug treatment of the cellular model, a mouse model and human iPSC derived neurons alleviate cellular and systemic deficits associated with tauP301L. Comparison of Septin filament architecture in disease conditions with and without the drug treatment indicate that excess Ca[2+] entry is a consequence of abnormal Septin filament architecture resulting in aberrant ER-PM contacts. The importance of membrane contacts for maintaining precise cellular signaling has been recognized previously. However, the molecular mechanism by which Septin filaments organize the ER-PM junctions to regulate Ca[2+] entry through Orai remains to be fully understood.},
}

@article {pmid39017993,
year = {2024},
author = {Darwish, AB and Salama, A and Younis, MM},
title = {Neuroprotective efficiency of celecoxib vesicular bilosomes for the management of lipopolysaccharide-induced Alzheimer in mice employing 2[3] full factorial design.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {39017993},
issn = {1568-5608},
abstract = {The aim of this study was to develop and evaluate bilosomes loaded with Celecoxib (CXB) for the efficient treatment of Alzheimer. The thin-film hydration approach was utilized in the formulation of CXB bilosomes (CXB-BLs). The study used a 2[3]-factorial design to investigate the impact of several formulation variables. Three separate parameters were investigated: bile salt type (X1), medication amount (X2), and lipid-bile salt ratio (X3). The dependent responses included entrapment efficiency (Y1: EE %), particle size (Y2: PS), and zeta potential (Y3: ZP). The formulation factors were statistically optimized using the Design-Expert[®] program. The vesicles demonstrated remarkable CXB encapsulation efficiency, ranging from 94.16 ± 1.91 to 98.38 ± 0.85%. The vesicle sizes ranged from 241.8 ± 6.74 to 352 ± 2.34 nm. The produced formulations have high negative zeta potential values, indicating strong stability. Transmission electron microscopy (TEM) revealed that the optimized vesicles had a spherical form. CXB release from BLs was biphasic, with the release pattern following Higuchi's model. In vivo studies confirmed the efficiency of CXB-BLs in management of lipopolysaccharide-induced Alzheimer as CXB-BLs ameliorated cognitive dysfunction, decreased acetylcholinesterase (AChE), and inhibited neuro-inflammation and neuro-degeneration through reducing Toll-like receptor (TLR4), and Interleukin-1β (IL-1β) levels. The findings suggested that the created CXB-BLs could be a potential drug delivery strategy for Alzheimer's treatment.},
}

@article {pmid39017902,
year = {2024},
author = {Li, J and Sun, L and Zhao, Y},
title = {Advances in non-coding RNA as a biomarker for obstructive sleep apnoea hypoventilation syndrome.},
journal = {Sleep & breathing = Schlaf & Atmung},
volume = {},
number = {},
pages = {},
pmid = {39017902},
issn = {1522-1709},
support = {202301AY070001-146//Yunnan Provincial Science and Technology Department/ ; KUST-PE2022004Y//Kunming University of Science and Technology, Basic Research Program/ ; },
abstract = {PURPOSE: Obstructive sleep apnoea hypoventilation syndrome (OSAHS) is a common sleep disorder that affects multiple body systems, which in turn is closely associated with cognitive dysfunction, diabetes mellitus, oncological cardiovascular diseases and metabolic disorders. In recent years, non-coding RNA (ncRNA) has emerged as a new opportunity for biomarker discovery. We therefore discuss the research progress and potential role of ncRNAs in obstructive sleep apnea hypoventilation syndrome.

METHODS: This review systematically searched relevant academic literature from PubMed, Web of Science and other databases. During the retrieval process, a combination of keywords such as "OSAHS", "ncRNA", "lncRNA", "miRAN", "circRNA" was used for search.

RESULTS: Circulating ncRNA has good area under the ROC curve, sensitivity and specificity in the diagnosis of OSAHS, and has the potential to become a diagnostic marker for OSAHS, while several circulating ncRNAs or circulating ncRNAs in combination with other tests such as the Obstructive Sleep Apnoea Screening Scale have a higher value of application as a test for OSAHS. Further analyses revealed that many circulating ncRNAs were significantly differentially expressed in the serum of OSAHS patients with different very severities, a potential marker for predicting the severity of OSAHS, and that the ncRNA content of patients' serum also had a significant effect during CPAP therapy, suggesting that it may have potential for therapeutic monitoring. Meanwhile, serum ncRNAs from patients have been shown to be effective in the diagnosis of OSAHS complications such as hypertension, Alzheimer's disease, acute myocardial infarction and atherosclerosis. The expression of up- or down-regulated ncRNAs can regulate different signalling pathways, which in turn affects various OSAHS complications such as pulmonary hypertension, diabetes mellitus, and cognitive dysfunction, and is expected to become a new direction for the treatment of these complications.

CONCLUSIONS: The changes in ncRNA expression in OSAHS patients are expected to be a novel biomarker for the diagnosis and treatment of OSAHS, and can also be used as a potential biomarker for the combination of diabetes mellitus, cardiovascular disease, respiratory disease, and cognitive dysfunction in OSAHS. It is believed that the continuous progress of ncRNA-related research is expected to promote the early detection, diagnosis and treatment of OSAHS and its complications.},
}

@article {pmid39015065,
year = {2024},
author = {Lansdall, CJ and Teng, E and Chague, J and Palanganda, R and Delmar, P and Smith, J and Cummings, JL and McDougall, F},
title = {Care partner-informed meaningful change thresholds for the Clinical Dementia Rating-Sum of Boxes for trials of early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14050},
pmid = {39015065},
issn = {1552-5279},
support = {//Genentech, Inc. and F. Hoffmann-La Roche Ltd/ ; },
abstract = {INTRODUCTION: Consensus definitions of meaningful within-patient change (MWPC) on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) are needed. Existing estimates use clinician-rated anchors in clinically diagnosed Alzheimer's disease (AD) populations. Incorporating the care partner perspective offers important insights, and evaluating biomarker-confirmed cohorts aligns estimates with ongoing trials.

METHODS: Anchor-based analyses were conducted to evaluate MWPC on the CDR-SB in early AD (Tauriel; NCT03289143) using Caregiver Global Impression of Change in memory or daily activities.

RESULTS: Across time points and anchors, mean CDR-SB changes associated with the "somewhat worse" category ranged from 1.50 to 2.12 in early AD, 1.07 to 2.06 in mild cognitive impairment-AD, and 1.79 to 2.25 in mild AD.

DISCUSSION: The proposed ranges are appropriate to define meaningful progression on the CDR-SB in similar cohorts and support the interpretation of treatment benefit through MWPC analyses. Thresholds should be calibrated to the context of use; lower/higher thresholds may be applicable in studies of earlier/later disease over shorter/longer durations.

HIGHLIGHTS: Within-patient CDR-SB change thresholds are provided using caregiver-rated anchors. 1.5 to 2.5 points may be an appropriate range in early AD trials of similar durations. Cumulative distribution function plots illustrate the benefit of a given treatment. When selecting thresholds, the target population and study design should be considered.},
}

@article {pmid39014454,
year = {2024},
author = {Cheng, Y and Chen, SF and Zhang, YR and Guo, Y and Wu, KM and Huang, YY and Aerqin, Q and Kuo, K and Li, HQ and Chen, SD and Liu, WS and Dong, Q and Yu, JT},
title = {Novel diagnostic and prognostic approach for rapidly progressive dementias: Indicators based on amyloid/tau/neurodegeneration (ATN) framework.},
journal = {CNS neuroscience & therapeutics},
volume = {30},
number = {7},
pages = {e14857},
pmid = {39014454},
issn = {1755-5949},
support = {2019074//Shanghai Talent Development Funding for The Project/ ; 21QA1408700//Shanghai Rising Star Program/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 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/ ; //the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education/ ; },
mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; Male ; Female ; Aged ; Middle Aged ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; Prognosis ; *Dementia/diagnosis/blood/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; *Disease Progression ; Creutzfeldt-Jakob Syndrome/diagnosis/blood/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid/blood ; Alzheimer Disease/diagnosis/blood/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs).

METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aβ42, Aβ40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014).

CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.},
}

Humans
*tau Proteins/blood/cerebrospinal fluid
Male
Female
Aged
Middle Aged
*Amyloid beta-Peptides/cerebrospinal fluid/blood
Prognosis
*Dementia/diagnosis/blood/cerebrospinal fluid
*Biomarkers/blood/cerebrospinal fluid
*Disease Progression
Creutzfeldt-Jakob Syndrome/diagnosis/blood/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid/blood
Alzheimer Disease/diagnosis/blood/cerebrospinal fluid
Aged, 80 and over

@article {pmid39014320,
year = {2024},
author = {Almasi, E and Heidarianpour, A and Keshvari, M},
title = {The interactive effects of different exercises and hawthorn consumption on the pain threshold of TMT-induced Alzheimer male rats.},
journal = {The journal of physiological sciences : JPS},
volume = {74},
number = {1},
pages = {36},
pmid = {39014320},
issn = {1880-6562},
mesh = {Animals ; Male ; *Alzheimer Disease/physiopathology/therapy/chemically induced ; Rats ; *Pain Threshold/drug effects ; *Physical Conditioning, Animal/physiology ; *Crataegus ; Plant Extracts/pharmacology ; Swimming ; Disease Models, Animal ; Rats, Sprague-Dawley ; },
abstract = {Exercise increases the pain threshold in healthy people. However, the pain threshold modulation effect of exercise and hawthorn is unclear because of its potential benefits in people with persistent pain, including those with Alzheimer's disease. Accordingly, after the induction of Alzheimer's disease by trimethyl chloride, male rats with Alzheimer's disease were subjected to a 12-week training regimen consisting of resistance training, swimming endurance exercises, and combined exercises. In addition, hawthorn extract was orally administered to the rats. Then, their pain threshold was evaluated using three Tail-flick, Hot-plate, and Formalin tests. Our results showed that Alzheimer's decreased the pain threshold in all three behavioral tests. Combined exercise with hawthorn consumption had the most statistically significant effect on Alzheimer's male rats' pain threshold in all three experiments. A combination of swimming endurance and resistance exercises with hawthorn consumption may modulate hyperalgesia in Alzheimer's rats. Future studies need to determine the effects of these factors on the treatment and/or management of painful conditions.},
}

Animals
Male
*Alzheimer Disease/physiopathology/therapy/chemically induced
Rats
*Pain Threshold/drug effects
*Physical Conditioning, Animal/physiology
*Crataegus
Plant Extracts/pharmacology
Swimming
Disease Models, Animal
Rats, Sprague-Dawley

@article {pmid39014255,
year = {2024},
author = {Wei, N and Zhang, LM and Xu, JJ and Li, SL and Xue, R and Ma, SL and Li, C and Sun, MM and Chen, KS},
title = {Astaxanthin Rescues Memory Impairments in Rats with Vascular Dementia by Protecting Against Neuronal Death in the Hippocampus.},
journal = {Neuromolecular medicine},
volume = {26},
number = {1},
pages = {29},
pmid = {39014255},
issn = {1559-1174},
support = {82001256//National Natural Science Foundation of China/ ; SBGJ202103052//The Henan Province Medical Science and Technology Research Project/ ; 182102310512//The Key R&D and Promotion Program of Henan Science and Technology Department/ ; 202102310354//The Key R&D and Promotion Program of Henan Science and Technology Department/ ; 222102310084//The Key R&D and Promotion Program of Henan Science and Technology Department/ ; },
mesh = {Animals ; *Xanthophylls/therapeutic use/pharmacology ; *Hippocampus/drug effects ; *Dementia, Vascular/drug therapy ; Rats ; Male ; *Memory Disorders/drug therapy/etiology ; *Oxidative Stress/drug effects ; *Neurons/drug effects ; *Apoptosis/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Rats, Sprague-Dawley ; Proto-Oncogene Proteins c-akt/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Maze Learning/drug effects ; Disease Models, Animal ; Signal Transduction/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Cell Death/drug effects ; Antioxidants/therapeutic use/pharmacology ; Morris Water Maze Test/drug effects ; },
abstract = {Vascular dementia (VaD) is a cognitive disorder characterized by a decline in cognitive function resulting from cerebrovascular disease. The hippocampus is particularly susceptible to ischemic insults, leading to memory deficits in VaD. Astaxanthin (AST) has shown potential therapeutic effects in neurodegenerative diseases. However, the mechanisms underlying its protective effects in VaD and against hippocampal neuronal death remain unclear. In this study, We used the bilateral common carotid artery occlusion (BCCAO) method to establish a chronic cerebral hypoperfusion (CCH) rat model of VaD and administered a gastric infusion of AST at 25 mg/kg per day for 4 weeks to explore its therapeutic effects. Memory impairments were assessed using Y-maze and Morris water maze tests. We also performed biochemical analyses to evaluate levels of hippocampal neuronal death and apoptosis-related proteins, as well as the impact of astaxanthin on the PI3K/Akt/mTOR pathway and oxidative stress. Our results demonstrated that AST significantly rescued memory impairments in VaD rats. Furthermore, astaxanthin treatment protected against hippocampal neuronal death and attenuated apoptosis. We also observed that AST modulated the PI3K/Akt/mTOR pathway, suggesting its involvement in promoting neuronal survival and synaptic plasticity. Additionally, AST exhibited antioxidant properties, mitigating oxidative stress in the hippocampus. These findings provide valuable insights into the potential therapeutic effects of AST in VaD. By elucidating the mechanisms underlying the actions of AST, this study highlights the importance of protecting hippocampal neurons and suggests potential targets for intervention in VaD. There are still some unanswered questions include long-term effects and optimal dosage of the use in human. Further research is warranted to fully understand the therapeutic potential of AST and its application in the clinical treatment of VaD.},
}

Animals
*Xanthophylls/therapeutic use/pharmacology
*Hippocampus/drug effects
*Dementia, Vascular/drug therapy
Rats
Male
*Memory Disorders/drug therapy/etiology
*Oxidative Stress/drug effects
*Neurons/drug effects
*Apoptosis/drug effects
*Neuroprotective Agents/therapeutic use/pharmacology
*Rats, Sprague-Dawley
Proto-Oncogene Proteins c-akt/metabolism
TOR Serine-Threonine Kinases/metabolism
Maze Learning/drug effects
Disease Models, Animal
Signal Transduction/drug effects
Phosphatidylinositol 3-Kinases/metabolism
Cell Death/drug effects
Antioxidants/therapeutic use/pharmacology
Morris Water Maze Test/drug effects

@article {pmid39013601,
year = {2024},
author = {Sandoval, KE and Witt, KA},
title = {Somatostatin: Linking Cognition and Alzheimer's Disease to Therapeutic Targeting.},
journal = {Pharmacological reviews},
volume = {},
number = {},
pages = {},
doi = {10.1124/pharmrev.124.001117},
pmid = {39013601},
issn = {1521-0081},
abstract = {Over four decades of research support the link between Alzheimer's disease (AD) and somatostatin (somatotropin-releasing inhibitory factor, SRIF). SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-beta peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation. Whereas, preclinical AD investigations show SRIF or SRIF-receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here we review the links between SRIF and AD, along with the therapeutic implications. Significance Statement Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer's disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin mediated processes has significant therapeutic potential for the treatment of Alzheimer's disease.},
}

@article {pmid39013512,
year = {2024},
author = {Zhang, T and Wu, J and Wang, Y and Zhang, H and Zhan, X},
title = {Alleviating neuronal inflammation induced by Aβ42 in SH-SY5Y through interaction with polysialic acid-oligomannuronate conjugate.},
journal = {International journal of biological macromolecules},
volume = {276},
number = {Pt 1},
pages = {133862},
doi = {10.1016/j.ijbiomac.2024.133862},
pmid = {39013512},
issn = {1879-0003},
abstract = {Amyloid beta (Aβ) aggregation is one of the distinctive pathological hallmarks of Alzheimer's disease (AD). Therefore, the development of effective inhibitors against Aβ aggregate formation offers great promise for the treatment of AD. In this study, we designed a novel negatively charged functionalized conjugate aimed at inhibiting Aβ42 aggregation and attenuating neurotoxicity by grafting polysialic acid with mannuronate oligosaccharide, a biocompatible glycan extracted from seaweeds, designated as polysialic acid-mannan conjugate (PSA-MOS). ThT, biological microscopy, TEM and CD confirmed the inhibition of Aβ42 aggregation by PSA-MOS, as well as its ability to inhibit the conformational transition of Aβ42 to β-sheet. CCK-8 assay demonstrated that PSA-MOS was not cytotoxic to SH-SY5Y (p < 0.05) and promoted cell proliferation. In the Aβ42-induced SH-SY5Y injury models, PSA-MOS dose-dependently ameliorated cytotoxicity (p < 0.0001) and significantly reduced the levels of inflammatory factors of IL-1β (p < 0.0001), IL-6 (p < 0.0001) and TNF-α (p < 0.05). MD simulations demonstrated that PSA-MOS effectively impeded the α-helix to β-sheet transition of the Aβ42 monomer via electrostatic interactions with its CTR and NTR regions. These findings demonstrate the therapeutic potential of PSA-MOS as promising glycoconjugate for the treatment of AD.},
}

@article {pmid39012787,
year = {2024},
author = {Gómez-Morales, A and Coon, DW and Joseph, RP and Pipe, T},
title = {Through Alzheimer's Eyes: A Virtual Pilot Intervention for Family Caregivers of People with Dementia.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/07317115.2024.2378774},
pmid = {39012787},
issn = {1545-2301},
abstract = {OBJECTIVE: To evaluate the feasibility and acceptability of a virtually delivered psychoeducational skill-building intervention for ADRD caregivers.

METHODS: A single-arm, pre-posttest pilot study design was employed to evaluate the intervention. Four 90-min group-based weekly sessions were combined with four individual coaching sessions via Zoom. Intervention components covered topics designed to reduce caregiver stress and distress, and a VR experience to help caregivers understand dementia. Data was gathered via REDCap pre- and post-intervention and through post-intervention interviews via Zoom.

RESULTS: Results (N = 20) from individual interviews, surveys, and treatment implementation strategies suggest strong feasibility and acceptability. Key change exploration indicated medium effect sizes and statistical significance in preparedness for caregiving (t(19) = 2.69, p = .015, d = 63), communication (t(19) = 2.45, p = .024, d = 0.55), and a medium effect size for the mindful attention awareness scale (t(19) = 0.48, p = (0.637, d = 0.54). Further, participants reported their perceptions of improvement in outcomes such as the ability to care, increased understanding of memory loss, and confidence.

CONCLUSIONS: Through Alzheimer's Eyes is a feasible and acceptable intervention that blends technology with skill-building strategies to help caregivers manage their stress and distress regardless of their location.

CLINICAL IMPLICATIONS: There is potential for interventions including VR to assist family caregivers in managing caregiving challenges and improve well-being.},
}

@article {pmid39012631,
year = {2024},
author = {Cai, C and Strickland, K and Knudsen, S and Tucker, SB and Chidrala, CS and Modugno, F},
title = {Alzheimer Disease and Related Dementia Following Hormone-Modulating Therapy in Patients With Breast Cancer.},
journal = {JAMA network open},
volume = {7},
number = {7},
pages = {e2422493},
pmid = {39012631},
issn = {2574-3805},
mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/drug therapy ; Aged ; *Alzheimer Disease/epidemiology ; Aged, 80 and over ; United States/epidemiology ; *Dementia/epidemiology ; *SEER Program ; Cohort Studies ; Risk Factors ; },
abstract = {IMPORTANCE: Hormone-modulating therapy (HMT) is a widely accepted treatment for hormone receptor-positive breast cancer, although its cognitive effects, including a potential link to Alzheimer disease and related dementias (ADRD), remain understudied.

OBJECTIVE: To investigate the association between HMT for breast cancer treatment and risk of developing ADRD in women aged 65 years or older.

This cohort study used a comprehensive dataset from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to identify patients who did and did not receive HMT treatment within 3 years after the initial diagnosis of breast cancer and assessed their risk of developing ADRD in later life. Individuals with a preexisting diagnosis of ADRD or receiving HMT before the diagnosis of breast cancer were excluded. This study was performed from June 2022 through January 2024.

EXPOSURE: Receipt of HMT.

MAIN OUTCOMES AND MEASURES: Risk of ADRD associated with HMT; associations of risk with age, self-identified race, and HMT type. Risk was measured using hazard ratios (HRs) with 95% CIs and adjusted for potential confounders such as demographic, sociocultural, and clinical variables.

RESULTS: Among 18 808 women aged 65 years and older diagnosed with breast cancer between 2007 and 2009 (1266 Black [6.7%], 16 526 White [87.9%], 1016 other [5.4%]), 12 356 (65.7%) received HMT within 3 years after diagnosis, while 6452 (34.3%) did not. The most common age group in both samples was the 75 to 79 years age group (HMT, 2721 women [22.0%]; no HMT, 1469 women [22.8%]), and the majority of women in both groups self-identified as White (HMT, 10 904 women [88.3%]; no HMT, 5622 women [87.1%]). During an average of 12 years of follow-up, 2926 (23.7%) of HMT users and 1802 (27.9%) of non-HMT users developed ADRD. HMT was associated with a 7% lower relative risk of ADRD overall (HR, 0.93; 95% CI, 0.88-0.98; P = .005). The association decreased with age and varied by race. The reduction in ADRD risk associated with HMT was greatest for women aged 65 to 74 years who self-identified as Black (HR, 0.76; 95% CI, 0.62-0.92). This association decreased among women aged 75 years or older (HR, 0.81; 95% CI, 0.67-0.98). Women aged 65 to 74 years who self-identified as White had an 11% relative risk reduction (HR, 0.89; 95% CI, 0.81-0.97), but the association disappeared for women aged 75 years or older (HR, 0.96; 95% CI, 0.90-1.02). Other races showed no significant association between HMT and ADRD. Age- and race-based associations also varied by HMT type.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study, hormone therapy was associated with protection against ADRD in women aged 65 years or older with newly diagnosed breast cancer; the decrease in risk was relatively greater for Black women and women under age 75 years, while the protective effect of HMT diminished with age and varied by race in women. When deciding to use HMT for breast cancer in women aged 65 years or more, clinicians should consider age, self-identified race, and HMT type in treatment decisions.},
}

Humans
Female
*Breast Neoplasms/epidemiology/drug therapy
Aged
*Alzheimer Disease/epidemiology
Aged, 80 and over
United States/epidemiology
*Dementia/epidemiology
*SEER Program
Cohort Studies
Risk Factors

@article {pmid39012444,
year = {2024},
author = {Owona, BA and Mary, A and Messi, AN and Ravichandran, KA and Mbing, JN and Pegnyemb, E and Moundipa, PF and Heneka, MT},
title = {Biflavonoid Methylchamaejasmin and Khaya grandifoliola Extract Inhibit NLRP3 Inflammasome in THP-1 Cell Model of Neuroinflammation.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {39012444},
issn = {1559-1182},
support = {HE3350/19-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Neuroinflammation is a common hallmark of Alzheimer's disease (AD), with NLRP3 inflammasome proven to be activated in microglia of AD patients' brains. In this study, a newly isolated biflavonoid (7,7'-di-O-methylchamaejasmin/M8) and a crude extract of the plant Khaya grandifoliola (KG) were investigated for their inhibitory effect on inflammasome activation. In preliminary experiments, M8 and KG showed no cytotoxicity on human macrophage-like differentiated THP-1 cells and exhibited anti-inflammatory inhibition of nitric oxide produced following lipopolysaccharide stimulation. Furthermore, M8 and KG blocked IL-1β and IL-18 production by reducing NLRP3 inflammasome components including NFκB, NLRP3, Caspase-1, pro-IL-1β, and pro-IL-18 at the mRNA and protein levels. Regarding the formation of ASC (apoptosis-associated speck-like protein containing a CARD) specks during inflammasome activation, the size and fluorescent intensity of the existing specks were unchanged across all treatment conditions. However, M8 and KG treatments were shown to prevent further speck formation. In addition, experiments on amyloid β phagocytosis showed that M8 and KG pretreatments can restore the phagocytic activity of THP-1 cells, which was impaired following inflammasome activation. Altogether, our findings describe for the first time a promising role of biflavonoids and KG extract in preventing inflammasome activation and protecting against neuroinflammation, a key factor in AD development.},
}

@article {pmid39012229,
year = {2024},
author = {Duan, LH and Li, LI and Wang, CB and Liu, QQ and Zhang, X and Wu, ZZ},
title = {Brain targeting efficacy of novel drug delivery system in the treatment of Alzheimer's disease.},
journal = {European review for medical and pharmacological sciences},
volume = {28},
number = {13},
pages = {3892-3904},
doi = {10.26355/eurrev_202407_36521},
pmid = {39012229},
issn = {2284-0729},
mesh = {*Alzheimer Disease/drug therapy ; *Chitosan/chemistry ; *Administration, Intranasal ; *Brain/metabolism/drug effects ; *Drug Delivery Systems ; Animals ; *Galantamine/administration & dosage/pharmacokinetics ; *Cholinesterase Inhibitors/administration & dosage ; Humans ; Rats ; Male ; Nanoparticle Drug Delivery System/chemistry ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group.

MATERIALS AND METHODS: Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration.

RESULTS: The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration.

CONCLUSIONS: This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.},
}

*Alzheimer Disease/drug therapy
*Chitosan/chemistry
*Administration, Intranasal
*Brain/metabolism/drug effects
*Drug Delivery Systems
Animals
*Galantamine/administration & dosage/pharmacokinetics
*Cholinesterase Inhibitors/administration & dosage
Humans
Rats
Male
Nanoparticle Drug Delivery System/chemistry

@article {pmid39012223,
year = {2024},
author = {Morrison, C and Oliver, MD and Kamal, F and Dadar, M and , },
title = {Beyond Hypertension: Examining Variable Blood Pressure's Role in Cognition and Brain Structure.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbae121},
pmid = {39012223},
issn = {1758-5368},
abstract = {OBJECTIVES: Hypertension or high blood pressure (BP) is one of the twelve modifiable risk factors that contribute to 40% of dementia cases that could be delayed or prevented. Although hypertension is associated with cognitive decline and structural brain changes, less is known about the long-term association between variable BP and cognitive/brain changes. This study examined the relationship between variable BP and longitudinal cognitive, white matter hyperintensity (WMH), gray matter (GM), and white matter (WM) volume change over time and post-mortem neuropathology.

METHODS: A total of 4,606 participants (32,776 follow-ups) from RADC Research Resource Sharing Hub (RUSH) and 2,114 participants (9,827 follow-ups) from Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. Participants were divided into one of three groups: normal, high, or variable BP. Linear mixed models investigated the relationship between BP and cognition, brain structure, and neuropathology.

RESULTS: Older adults with variable BP exhibited the highest rate of cognitive decline followed by high and then normal BP. Increased GM volume loss and WMH burden was also observed in variable compared to high and normal BP. In post-mortem neuropathology, both variable and high BP had increased rates compared to normal BP. All the results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings.

DISCUSSION: Damages potentially associated with variable BP may reduce resilience to future dementia related pathology and increased risk of dementia more than that caused by high BP. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population.},
}

@article {pmid39011039,
year = {2024},
author = {Wang, C and Wang, J and Zhu, Z and Hu, J and Lin, Y},
title = {Spotlight on pro-inflammatory chemokines: regulators of cellular communication in cognitive impairment.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1421076},
pmid = {39011039},
issn = {1664-3224},
mesh = {Humans ; *Cognitive Dysfunction/etiology/immunology/metabolism ; *Chemokines/metabolism ; Animals ; *Cell Communication ; Inflammation/immunology/metabolism ; Inflammation Mediators/metabolism ; },
abstract = {Cognitive impairment is a decline in people's ability to think, learn, and remember, and so forth. Cognitive impairment is a global health challenge that affects the quality of life of thousands of people. The condition covers a wide range from mild cognitive impairment to severe dementia, which includes Alzheimer's disease (AD) and Parkinson's disease (PD), among others. While the etiology of cognitive impairment is diverse, the role of chemokines is increasingly evident, especially in the presence of chronic inflammation and neuroinflammation. Although inflammatory chemokines have been linked to cognitive impairment, cognitive impairment is usually multifactorial. Researchers are exploring the role of chemokines and other inflammatory mediators in cognitive dysfunction and trying to develop therapeutic strategies to mitigate their effects. The pathogenesis of cognitive disorders is very complex, their underlying causative mechanisms have not been clarified, and their treatment is always one of the challenges in the field of medicine. Therefore, exploring its pathogenesis and treatment has important socioeconomic value. Chemokines are a growing family of structurally and functionally related small (8-10 kDa) proteins, and there is growing evidence that pro-inflammatory chemokines are associated with many neurobiological processes that may be relevant to neurological disorders beyond their classical chemotactic function and play a crucial role in the pathogenesis and progression of cognitive disorders. In this paper, we review the roles and regulatory mechanisms of pro-inflammatory chemokines (CCL2, CCL3, CCL4, CCL5, CCL11, CCL20, and CXCL8) in cognitive impairment. We also discuss the intrinsic relationship between the two, hoping to provide some valuable references for the treatment of cognitive impairment.},
}

Humans
*Cognitive Dysfunction/etiology/immunology/metabolism
*Chemokines/metabolism
Animals
*Cell Communication
Inflammation/immunology/metabolism
Inflammation Mediators/metabolism

@article {pmid39009828,
year = {2024},
author = {Khare, N and Barot, M and Singh, S and Jain, T},
title = {Network Pharmacology Reveals Key Targets and Pathways of Madhuca longifolia for Potential Alzheimer's Disease Treatment.},
journal = {Cell biochemistry and biophysics},
volume = {},
number = {},
pages = {},
pmid = {39009828},
issn = {1559-0283},
abstract = {Madhuca longifolia, commonly known as the mahua tree, has been traditionally used in medicine due to its anti-inflammatory, anti-diabetic, and antimicrobial properties. Its active compounds help in managing diabetes, alleviating cognitive impairment associated with Alzheimer's disease. Nonetheless, the exact neuroprotective mechanism of Madhuca longifolia against Alzheimer's disease remains unclear. This study looked into possible methods by which Madhuca longifolia protects against Alzheimer's disease using network pharmacology, molecular docking and molecular dynamic simulations studies. By applying pre-screening of active constituents, target prediction, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis, our study found that Madhuca longifolia is related to eight active ingredients (Ascorbic acid, Riboflavin, Pantothenic acid, (4 R)-2beta,3beta,23-trihydroxy-oleana-5,12-dien-28-oic acid, Quercetin, Nicotinic acid, Bassiaic acid Thiamine) and 272 common gene targets, with significant involvement in pathways such as PI3K-Akt signaling and neuroactive ligand-receptor interaction. Network analysis demonstrated how Madhuca longifolia can prevent AD by modifying important signalling networks, which may be one of the molecular mechanisms driving the plant's effectiveness against the disease. Molecular docking studies revealed that there were robust binding abilities of Quercetin, Riboflavin and Pantothenic acid to key target proteins AKT1, JUN, and STAT3. Later, molecular dynamic simulations was done to examine the successful activity of the active compounds against potential targets, and it was found that AKT1 and AKT1-Quercetin complex became stable at 260 ps. It may be seen through the study that quercetin may act as a good inhibitor for treatment. This thorough investigation provides a strong basis for future research and development efforts by advancing our understanding of Madhuca longifolia medicinal potential in Alzheimer's disease.},
}

@article {pmid39009798,
year = {2024},
author = {Khan, MS and Khan, Z and Jabir, NR and Mehan, S and Suhail, M and Zaidi, SK and Zughaibi, TA and Abid, M and Tabrez, S},
title = {Synthesis and Neurobehavioral Evaluation of a Potent Multitargeted Inhibitor for the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {39009798},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) poses a significant health challenge worldwide, affecting millions of individuals, and projected to increase further as the global population ages. Current pharmacological interventions primarily target acetylcholine deficiency and amyloid plaque formation, but offer limited efficacy and are often associated with adverse effects. Given the multifactorial nature of AD, there is a critical need for novel therapeutic approaches that simultaneously target multiple pathological pathways. Targeting key enzymes involved in AD pathophysiology, such as acetylcholinesterase, butyrylcholinesterase, beta-site APP cleaving enzyme 1 (BACE1), and gamma-secretase, is a potential strategy to mitigate disease progression. To this end, our research group has conducted comprehensive in silico screening to identify some lead compounds, including IQ6 (SSZ), capable of simultaneously inhibiting the enzymes mentioned above. Building upon this foundation, we synthesized SSZ, a novel multitargeted ligand/inhibitor to address various pathological mechanisms underlying AD. Chemically, SSZ exhibits pharmacological properties conducive to AD treatment, featuring pyrrolopyridine and N-cyclohexyl groups. Preclinical experimental evaluation of SSZ in AD rat model showed promising results, with notable improvements in behavioral and cognitive parameters. Specifically, SSZ treatment enhanced locomotor activity, ameliorated gait abnormalities, and improved cognitive function compared to untreated AD rats. Furthermore, brain morphological analysis demonstrated the neuroprotective effects of SSZ, attenuating Aβ-induced neuronal damage and preserving brain morphology. Combined treatment of SSZ and conventional drugs (DON and MEM) showed synergistic effects, suggesting a potential therapeutic strategy for AD management. Overall, our study highlights the efficacy of multitargeted ligands like SSZ in combating AD by addressing the complex etiology of the disease. Further research is needed to elucidate the full therapeutic potential of SSZ and the exploration of similar compounds in clinical settings, offering hope for an effective AD treatment in the future.},
}

@article {pmid39009412,
year = {2024},
author = {Stevenson, M and Hebron, ML and Liu, X and Balaraman, K and Wolf, C and Moussa, C},
title = {c-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer's disease.},
journal = {Life science alliance},
volume = {7},
number = {10},
pages = {},
pmid = {39009412},
issn = {2575-1077},
support = {TL1 TR001431/TR/NCATS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Mice, Transgenic ; Mice ; *Disease Models, Animal ; *Proto-Oncogene Proteins c-kit/metabolism ; *Microglia/drug effects/metabolism ; Autophagy/drug effects ; Humans ; Amyloid beta-Peptides/metabolism ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Brain/metabolism/drug effects/pathology ; Mast Cells/drug effects/metabolism ; tau Proteins/metabolism ; Plaque, Amyloid/metabolism/drug therapy ; Behavior, Animal/drug effects ; Male ; },
abstract = {Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/β, whereas BK40197 also differentially binds to FYVE finger-containing phosphoinositide kinase (PIKFYVE). Both compounds penetrate the CNS, and treatment with these drugs inhibited the maturation of peripheral mast cells in transgenic mice, correlating with cognitive improvements on measures of memory and anxiety. In the brain, microglial activation was profoundly attenuated and amyloid-beta and tau were reduced via autophagy. Multi-kinase inhibition, including c-KIT, exerts multifunctional effects to reduce neurodegenerative pathology via autophagy and microglial activity and may represent a potential therapeutic option for neurodegeneration.},
}

*Alzheimer Disease/drug therapy/metabolism
Animals
*Mice, Transgenic
Mice
*Disease Models, Animal
*Proto-Oncogene Proteins c-kit/metabolism
*Microglia/drug effects/metabolism
Autophagy/drug effects
Humans
Amyloid beta-Peptides/metabolism
Protein Kinase Inhibitors/pharmacology/therapeutic use
Brain/metabolism/drug effects/pathology
Mast Cells/drug effects/metabolism
tau Proteins/metabolism
Plaque, Amyloid/metabolism/drug therapy
Behavior, Animal/drug effects
Male

@article {pmid39008616,
year = {2024},
author = {Cai, H and Zhao, T and Pang, Y and Fu, X and Ren, Z and Quan, S and Jia, L},
title = {Systemic inflammatory markers in ageing, Alzheimer's disease and other dementias.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awae230},
pmid = {39008616},
issn = {1460-2156},
abstract = {Systemic inflammation with alterations in inflammatory markers is involved in aging and Alzheimer's disease. However, few studies have investigated the longitudinal trajectories of systemic inflammatory markers during aging and Alzheimer's disease, and specific markers contributing to Alzheimer's disease remain undetermined. In this study, a longitudinal cohort (cohort 1: n = 290; controls, 136; preclinical Alzheimer's disease, 154) and a cross-sectional cohort (cohort 2: n = 351; controls, 62; Alzheimer's disease, 63; vascular dementia, 58; Parkinson's disease dementia, 56; behavioural variant frontotemporal dementia, 57; dementia with Lewy bodies, 55) were included. Plasma levels of inflammatory markers were measured every 2 years during a 10-year follow-up in the longitudinal cohort and once in the cross-sectional cohort. The study demonstrated that the inflammatory markers significantly altered during both aging and the development of Alzheimer's disease. However, only complement C3, interleukin-1β, and interleukin-6 exhibited significant changes in participants with preclinical Alzheimer's disease, and their longitudinal changes were significantly associated with the development of Alzheimer's disease compared to controls over the 10-year follow-up. In the cross-sectional cohort, complement C3 demonstrates specificity to Alzheimer's disease, while interleukin-1β and interleukin-6 were also altered in other dementias. The study provides a new perspective on the involvement of inflammatory markers in the aging process and the development of Alzheimer's disease, implying that regulating inflammation may have a pivotal role in promoting successful aging and in the prevention and treatment of Alzheimer's disease.},
}

@article {pmid39008170,
year = {2024},
author = {Arora, R and Deshmukh, R},
title = {Embelin Mitigates Amyloid-β-Induced Neurotoxicity and Cognitive Impairment in Rats: Potential Therapeutic Implications for Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {39008170},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is a significant form of dementia. Embelin (EMB) is a natural compound with varied actions that could help prevent AD pathology. Herein, we have investigated the neuroprotective potential of EMB against Aβ1-42-induced neurotoxicity in rats. In this experiment, Alzheimer-like dementia was induced in rats by infusing Aβ1-42 oligomers directly into the brain's ventricles. Subsequently, the Aβ1-42-intoxicated rats received treatment with varying doses of EMB (2.5, 5, and 10 mg/kg, administered intraperitoneally) over 2 weeks. The spatial and non-spatial memory of animals was assessed at different time intervals, and various biochemical, neurochemical, and neuroinflammatory parameters in the hippocampal brain tissue of the rats were analyzed. Infusion of Aβ1-42 in rat brain caused cognitive impairment and was accompanied by increased acetylcholinesterase activity, oxidative stress, and elevated levels of pro-inflammatory cytokines (such as TNF-α, IL-1β, and IL-6) in the hippocampal tissue. Moreover, a significant decline in the levels of monoamines and an imbalance of GABA and glutamate levels were also observed. EMB treatment significantly mitigated Aβ1-42-induced cognitive deficit and other biochemical changes, including Aβ levels. The EMB-treated rats showed improved learning and consolidation of memory. EMB also attenuated Aβ-induced oxidative stress and neuroinflammation and restored the levels of monoamines and the balance between GABA and glutamate. The observed cognitive benefits following EMB treatment in Aβ1-42-infused rats may be attributed to its antioxidant and anti-inflammatory properties and ability to restore hippocampal neurochemistry and Aβ levels. The above findings indicate the therapeutic potential of EMB in neurodegenerative pathologies associated with cognitive decline, such as Alzheimer's disease.},
}

@article {pmid39007845,
year = {2024},
author = {Sharma, P and Kumari, P and Sharma, M and Sharma, R and Paliwal, A and Srivastava, S and Ashique, S and Bhowmick, M and Adnan, M and Mir, RH},
title = {Therapeutic potential of Aloe vera-coated curcumin encapsulated nanoparticles in an Alzheimer-induced mice model: behavioural, biochemical and histopathological evidence.},
journal = {Journal of microencapsulation},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/02652048.2024.2373715},
pmid = {39007845},
issn = {1464-5246},
abstract = {OBJECTIVE: The main purpose of the present study was to evaluate the therapeutic efficacy of Aloe vera-coated curcumin encapsulated nanoparticles in mitigating Alzheimer's disease progression in mice, by examining behavioural changes, biochemical markers, and histopathological alterations, thus elucidating its potential as a treatment strategy.

METHODS: The green synthesis method was used to synthesise this nanoformulation, which was then characterised using a variety of techniques, including percentage encapsulation efficacy, UV-visible spectroscopy, DLS, FT-IR, FESEM, and EDX. Several in-vivo assessments, including behavioural evaluations, dose optimisation studies, oxidative stress marker estimation, and histological studies, were conducted to determine the potential therapeutic impact of nanoformulation on the Alzheimer-induced mice model.

RESULTS: The synthesised nanoparticles show a mean diameter of 76.12 nm ±1.23, a PDI of 0.313 ± 0.02, a zeta potential of 6.27 ± 0.65 mV, and the percentage encapsulation efficiency between 90% and 95% indicating good stability of synthesised nanoformulation. With the help of Morris water maze, Y-maze, and novel object recognition assay, the learning capacity and memory were assessed, and the results show that the synthesised nanoformulation significantly decreased the transfer latency to reach baited arm or to the hidden platform within 7 days.

CONCLUSION: The formulation demonstrated significant biochemical benefits and remarkable cognitive advantages, establishing it as a prospective therapeutic intervention option that is both safe and effective.},
}

@article {pmid39007781,
year = {2024},
author = {Tinkov, OV and Osipov, VN and Kolotaev, AV and Khachatryan, DS and Grigorev, VY},
title = {HT_PREDICT: a machine learning-based computational open-source tool for screening HDAC6 inhibitors.},
journal = {SAR and QSAR in environmental research},
volume = {35},
number = {6},
pages = {505-530},
doi = {10.1080/1062936X.2024.2371155},
pmid = {39007781},
issn = {1029-046X},
mesh = {*Quantitative Structure-Activity Relationship ; *Histone Deacetylase 6/antagonists & inhibitors ; *Histone Deacetylase Inhibitors/chemistry/pharmacology ; *Machine Learning ; Humans ; Support Vector Machine ; Neural Networks, Computer ; },
abstract = {Histone deacetylase 6 (HDAC6) is a promising drug target for the treatment of human diseases such as cancer, neurodegenerative diseases (in particular, Alzheimer's disease), and multiple sclerosis. Considerable attention is paid to the development of selective non-toxic HDAC6 inhibitors. To this end, we successfully form a set of 3854 compounds and proposed adequate regression QSAR models for HDAC6 inhibitors. The models have been developed using the PubChem, Klekota-Roth, 2D atom pair fingerprints, and RDkit descriptors and the gradient boosting, support vector machines, neural network, and k-nearest neighbours methods. The models are integrated into the developed HT_PREDICT application, which is freely available at https://htpredict.streamlit.app/. In vitro studies have confirmed the predictive ability of the proposed QSAR models integrated into the HT_PREDICT web application. In addition, the virtual screening performed with the HT_PREDICT web application allowed us to propose two promising inhibitors for further investigations.},
}

*Quantitative Structure-Activity Relationship
*Histone Deacetylase 6/antagonists & inhibitors
*Histone Deacetylase Inhibitors/chemistry/pharmacology
*Machine Learning
Humans
Support Vector Machine
Neural Networks, Computer

@article {pmid39007605,
year = {2024},
author = {Blokina, I and Iluykov, E and Myagkov, D and Tuktarov, D and Popov, S and Inozemzev, T and Fedosov, I and Shirokov, A and Terskov, A and Dmitrenko, A and Evsyukova, A and Zlatogorskaya, D and Adushkina, V and Tuzhilkin, M and Manzhaeva, M and Krupnova, V and Dubrovsky, A and Elizarova, I and Tzoy, M and Semyachkina-Glushkovskaya, O},
title = {Photobiomodulation under Electroencephalographic Controls of Sleep for Stimulation of Lymphatic Removal of Toxins from Mouse Brain.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {208},
pages = {},
doi = {10.3791/67035},
pmid = {39007605},
issn = {1940-087X},
mesh = {Animals ; Mice ; *Brain/radiation effects ; *Mice, Inbred BALB C ; *Electroencephalography/methods ; *Sleep/physiology/radiation effects ; Low-Level Light Therapy/methods ; Amyloid beta-Peptides/metabolism ; Lymphatic Vessels/radiation effects/physiology ; },
abstract = {The meningeal lymphatic vessels (MLVs) play an important role in the removal of toxins from the brain. The development of innovative technologies for the stimulation of MLV functions is a promising direction in the progress of the treatment of various brain diseases associated with MLV abnormalities, including Alzheimer's and Parkinson's diseases, brain tumors, traumatic brain injuries, and intracranial hemorrhages. Sleep is a natural state when the brain's drainage processes are most active. Therefore, stimulation of the brain's drainage and MLVs during sleep may have the most pronounced therapeutic effects. However, such commercial technologies do not currently exist. This study presents a new portable technology of transcranial photobiomodulation (tPBM) under electroencephalographic (EEG) control of sleep designed to photo-stimulate removal of toxins (e.g., soluble amyloid beta (Aβ)) from the brain of aged BALB/c mice with the ability to compare the therapeutic effectiveness of different optical resources. The technology can be used in the natural condition of a home cage without anesthesia, maintaining the motor activity of mice. These data open up new prospects for developing non-invasive and clinically promising photo-technologies for the correction of age-related changes in the MLV functions and brain's drainage processes and for effectively cleansing brain tissues from metabolites and toxins. This technology is intended both for preclinical studies of the functions of the sleeping brain and for developing clinically relevant treatments for sleep-related brain diseases.},
}

Animals
Mice
*Brain/radiation effects
*Mice, Inbred BALB C
*Electroencephalography/methods
*Sleep/physiology/radiation effects
Low-Level Light Therapy/methods
Amyloid beta-Peptides/metabolism
Lymphatic Vessels/radiation effects/physiology

@article {pmid39007352,
year = {2024},
author = {Cardinali, CAEF and Martins, YA and Moraes, RCM and Costa, AP and Alencar, MB and Silber, AM and Torrão, AS},
title = {Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer's-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00113},
pmid = {39007352},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative process, also considered a metabolic condition due to alterations in glucose metabolism and insulin signaling pathways in the brain, which share similarities with diabetes. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analog, in the early stages of the neurodegenerative process in a sporadic model of Alzheimer's-like disease induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days reversed the cognitive impairment in short- and long-term memories caused by STZ in rodents. We attribute these effects to BFT's ability to modulate glucose transporters type 1 and 3 (GLUT1 and GLUT3) in the hippocampus, inhibit GSK3 activity in the hippocampus, and modulate the insulin signaling in the hippocampus and entorhinal cortex, as well as reduce the activation of apoptotic pathways (BAX) in the hippocampus. Therefore, BFT emerges as a promising and accessible intervention in the initial treatment of conditions similar to AD.},
}

@article {pmid39007083,
year = {2024},
author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM},
title = {Superoxide dismutase and neurological disorders.},
journal = {IBRO neuroscience reports},
volume = {16},
number = {},
pages = {373-394},
pmid = {39007083},
issn = {2667-2421},
abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.},
}

@article {pmid39006977,
year = {2024},
author = {Abdollahi, Z and Nejabat, M and Abnous, K and Hadizadeh, F},
title = {The therapeutic value of thiazole and thiazolidine derivatives in Alzheimer's disease: a systematic literature review.},
journal = {Research in pharmaceutical sciences},
volume = {19},
number = {1},
pages = {1-12},
pmid = {39006977},
issn = {1735-5362},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a common neurodegenerative disease and the fifth leading cause of death among the elderly. The development of drugs for AD treatment is based on inhibiting cholinesterase (ChE) activity and inhibiting amyloid-beta peptide and tau protein aggregations. Many in vitro findings have demonstrated that thiazole-and thiazolidine-based compounds have a good inhibitory effect on ChE and other elements involved in the AD pathogenicity cascade.

EXPERIMENTAL APPROACH: In the present review, we collected available documents to verify whether these synthetic compounds can be a step forward in developing new medications for AD. A systematic literature search was performed in major electronic databases in April 2021. Twenty-eight relevant in vitro and in vivo studies were found and used for data extraction.

FINDINGS/RESULTS: Findings demonstrated that thiazole-and thiazolidine-based compounds could ameliorate AD's pathologic condition by affecting various targets, including inhibition of ChE activity, amyloid-beta, and tau aggregation in addition to cyclin-dependent kinase 5/p25, beta-secretase-1, cyclooxygenase, and glycogen synthase kinase-3β.

CONCLUSION AND IMPLICATIONS: Due to multitarget effects at micromolar concentration, this review demonstrated that these synthetic compounds could be considered promising candidates for developing anti-Alzheimer drugs.},
}

@article {pmid39006824,
year = {2024},
author = {Schatz, S and Gutiérrez, GR},
title = {Enhancing socio-communicative functions in an MCI patient with intra-nasal insulin: a case report.},
journal = {Frontiers in psychiatry},
volume = {15},
number = {},
pages = {1326702},
pmid = {39006824},
issn = {1664-0640},
abstract = {This report examines extended intra-nasal insulin treatment [INI] for an Insulin Resistant early Mild Cognitive Impairment [MCI] patient. Patient [EJ] also had medial temporal lobe [MTL] damage, poor short-term memory, significant irritability, and social and linguistic withdrawal at treatment start. Compared to baseline, nine months INI treatment increased grey matter volume, lowered beta-amyloid levels, and improved MCI and FAS scores. Patient also increased pragmatic capacities in social conversation and procedural memory. These findings align with results from prior clinical trials on INI and suggest that treatment can slow neurodegenerative disease progression in early MCI patients.},
}

@article {pmid39006764,
year = {2024},
author = {Yang, C and Liu, G and Chen, X and Le, W},
title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.},
journal = {MedComm},
volume = {5},
number = {7},
pages = {e638},
pmid = {39006764},
issn = {2688-2663},
abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.},
}

@article {pmid39006715,
year = {2024},
author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J},
title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.},
journal = {Cureus},
volume = {16},
number = {6},
pages = {e62310},
pmid = {39006715},
issn = {2168-8184},
abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.},
}

@article {pmid39005845,
year = {2024},
author = {Canoy, RJ and Sy, JC and Deguit, CD and Castro, CB and Dimaapi, LJ and Panlaqui, BG and Perian, W and Yu, J and Velasco, JM and Sevilleja, JE and Gibson, A},
title = {Non-coding RNAs involved in the molecular pathology of Alzheimer's disease: a systematic review.},
journal = {Frontiers in neuroscience},
volume = {18},
number = {},
pages = {1421675},
pmid = {39005845},
issn = {1662-4548},
abstract = {UNLABELLED: Alzheimer's disease (AD) is the leading cause of dementia globally, having a pathophysiology that is complex and multifactorial. Recent findings highlight the significant role of non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs) in the molecular mechanisms underlying AD. These ncRNAs are involved in critical biological processes such as cell proliferation, apoptosis, oxidative stress, amyloid-beta aggregation, tau phosphorylation, neuroinflammation, and autophagy, which are pivotal in AD development and progression. This systematic review aims to consolidate current scientific knowledge on the role of ncRNAs in AD, making it the first to encompass the four types of ncRNAs associated with the disease. Our comprehensive search and analysis reveal that ncRNAs not only play crucial roles in the pathogenesis of AD but also hold potential as biomarkers for its early detection and as novel therapeutic targets. Specifically, the findings underscore the significance of miRNAs in regulating genes involved in key AD pathways such as activin receptor signaling pathway, actomyosin contractile ring organization, and advanced glycation endproducts-receptor advanced glycation endproducts (AGE-RAGE) signaling pathway. This review also highlights the potential of ncRNAs in unveiling novel diagnostic and therapeutic strategies, emphasizing the need for further research to validate their clinical utility. Our systematic exploration provides a foundation for future bioinformatic analyses and the development of ncRNA-based precision medicine approaches for AD, offering new insights into the disease's molecular pathology and paving the way for innovative treatment strategies.

PROSPERO, https://www.crd.york.ac.uk/prospero/, CRD42022355307.},
}

@article {pmid39005831,
year = {2024},
author = {Anh Phan, DT and Tran, HT and Le, HP and Khuong, TH and Ha, HT and Nguyen, DT and Nguyen, GT and Le, MV and Ly, TH},
title = {Exploring the Therapeutic Potential of Camellia longii Orel & Luu Leaf Extracts for Memory Loss in Alzheimer's Disease: Novel Findings and Functional Food Applications.},
journal = {ACS omega},
volume = {9},
number = {27},
pages = {29651-29665},
pmid = {39005831},
issn = {2470-1343},
abstract = {Novel research on the chemical compositions and biochemical activities of Camellia longii Orel and Luu leaf extracts revealed valuable resources with potential applications in Alzheimer's disease treatment. Qualitative phytochemicals detected various compound groups, including polyphenols, saponins, tannins, flavonoids, alkaloids, amino acids, coumarins, and polysaccharides. HPLC-MS identified 23 compounds in C. longii leaves with compounds found at significant levels, including epicatechin gallate (17.12%), tryptophan (13.73%), isovitexin (12.91%), gallic acid (3.06%), and quercetin (3.06%). Interestingly, the ethanol extract (CLL-Ew) exhibited the highest extraction yield (26.6%) and potent antioxidant and acetylcholinesterase (AChE) inhibitory effects in vitro. In the Drosophila melanogaster model, CLL-Ew improved longevity, movement, and memory by reducing malondialdehyde and increasing glutathione levels. Docking simulations suggested that the above compounds bind tightly to AChE's active site, potentially contributing to memory enhancement. Interestingly, observations of male and female mice after administration of a dose of 5000 mg/kg C. longii leaf extract were recorded normally throughout the 14 day experiment. These findings highlight the potential of C. longii leaf extracts in functional foods and therapeutic interventions for memory impairment prevention and treatment.},
}

@article {pmid39005733,
year = {2024},
author = {Gravandi, MM and Hosseini, SZ and Alavi, SD and Noori, T and Sureda, A and Amirian, R and Farzaei, MH and Shirooie, S},
title = {The Protective Effects of Pistacia Atlantica Gum in a Rat Model of Aluminum Chloride-Induced Alzheimer's Disease via Affecting BDNF and NF-kB.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {23},
number = {1},
pages = {e142203},
pmid = {39005733},
issn = {1726-6890},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, including deficits in memory and other cognitive functions. Oxidative stress and free radical damage play significant roles in its pathogenesis. This study aimed to investigate the potential anti-inflammatory and neuroprotective effects of Pistacia atlantica gum (administered at doses of 50 and 100 mg/kg for 14 days) in a rat model of AD induced by aluminum chloride (AlCl3). Behavioral changes were assessed using open field, passive avoidance, and elevated plus maze tests. Additionally, nitrite levels, nuclear factor-kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), and immunostaining were evaluated. Administration of P. atlantica gum significantly increased step-through latency in the passive avoidance test (P < 0.01 and P < 0.001), enhanced mobility in the open field test (P < 0.01 and P < 0.001), and reduced anxiety-like behaviors in the elevated plus maze (P < 0.001) compared to the AlCl3 group. Treatment with the gum partially normalized the elevated levels of NF-κB and the decreased levels of BDNF caused by AlCl3 exposure. Our findings suggest that P. atlantica gum administration may alleviate oxidative stress, neuroinflammation, and cognitive impairment in AD rats.},
}

@article {pmid39005433,
year = {2024},
author = {Carrillo, E and Romero, AM and Gonzalez, CU and Turcu, AL and Chen, SR and Chen, H and Pan, HL and Vázquez, S and Twomey, EC and Jayaraman, V},
title = {Memantine Inhibits Calcium-Permeable AMPA Receptors.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.02.601784},
pmid = {39005433},
issn = {2692-8205},
abstract = {Memantine is an US Food and Drug Administration (FDA) approved drug that selectively inhibits NMDA-subtype ionotropic glutamate receptors (NMDARs) for treatment of dementia and Alzheimer's. NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine reverses a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder and inhibits CP-AMPARs in nerve injury. Our findings alter the paradigm for the memantine mechanism of action and provide a blueprint for therapeutic approaches targeting CP-AMPARs.},
}

@article {pmid39005389,
year = {2024},
author = {Goettemoeller, AM and Banks, E and Kumar, P and Olah, VJ and McCann, KE and South, K and Ramelow, CC and Eaton, A and Duong, DM and Seyfried, NT and Weinshenker, D and Rangaraju, S and Rowan, MJ},
title = {Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.11.06.565629},
pmid = {39005389},
issn = {2692-8205},
abstract = {Preventative treatment for Alzheimer's Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer's Disease remain unknown. In human patients with Alzheimer's Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer's Disease. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type-specific proteomics coupled with ex vivo and in vivo electrophysiology, we uncovered differential susceptibility to human-specific amyloid precursor protein (hAPP) in a model of sporadic Alzheimer's. Unexpectedly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin (PV) interneurons, rather than the suspected layer II excitatory neurons. This vulnerability of entorhinal PV interneurons is specific to hAPP, as it could not be recapitulated with increased murine APP expression. However, partial replication of the findings could be seen after introduction of a murine APP chimera containing a humanized amyloid-beta sequence. Surprisingly, neurons in the Somatosensory Cortex showed no such vulnerability to adult-onset hAPP expression. hAPP-induced hyperexcitability in entorhinal cortex could be ameliorated by enhancing PV interneuron excitability in vivo. Co-expression of human Tau with hAPP decreased circuit hyperexcitability, but at the expense of increased pathological tau species. This study suggests early disease interventions targeting non-excitatory cell types may protect regions with early vulnerability to pathological symptoms of Alzheimer's Disease and downstream cognitive decline.},
}

@article {pmid39005357,
year = {2024},
author = {Yang, Y and Yu, K and Gao, S and Yu, S and Xiong, D and Qin, C and Chen, H and Tang, J and Tang, N and Zhu, H},
title = {Alzheimer's Disease Knowledge Graph Enhances Knowledge Discovery and Disease Prediction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.03.601339},
pmid = {39005357},
issn = {2692-8205},
abstract = {BACKGROUND: Alzheimer's disease (AD), a progressive neurodegenerative disorder, continues to increase in prevalence without any effective treatments to date. In this context, knowledge graphs (KGs) have emerged as a pivotal tool in biomedical research, offering new perspectives on drug repurposing and biomarker discovery by analyzing intricate network structures. Our study seeks to build an AD-specific knowledge graph, highlighting interactions among AD, genes, variants, chemicals, drugs, and other diseases. The goal is to shed light on existing treatments, potential targets, and diagnostic methods for AD, thereby aiding in drug repurposing and the identification of biomarkers.

RESULTS: We annotated 800 PubMed abstracts and leveraged GPT-4 for text augmentation to enrich our training data for named entity recognition (NER) and relation classification. A comprehensive data mining model, integrating NER and relationship classification, was trained on the annotated corpus. This model was subsequently applied to extract relation triplets from unannotated abstracts. To enhance entity linking, we utilized a suite of reference biomedical databases and refine the linking accuracy through abbreviation resolution. As a result, we successfully identified 3,199,276 entity mentions and 633,733 triplets, elucidating connections between 5,000 unique entities. These connections were pivotal in constructing a comprehensive Alzheimer's Disease Knowledge Graph (ADKG). We also integrated the ADKG constructed after entity linking with other biomedical databases. The ADKG served as a training ground for Knowledge Graph Embedding models with the high-ranking predicted triplets supported by evidence, underscoring the utility of ADKG in generating testable scientific hypotheses. Further application of ADKG in predictive modeling using the UK Biobank data revealed models based on ADKG outperforming others, as evidenced by higher values in the areas under the receiver operating characteristic (ROC) curves.

CONCLUSION: The ADKG is a valuable resource for generating hypotheses and enhancing predictive models, highlighting its potential to advance AD's disease research and treatment strategies.},
}

@article {pmid39005334,
year = {2024},
author = {Sonsalla, MM and Babygirija, R and Johnson, M and Cai, S and Cole, M and Yeh, CY and Grunow, I and Liu, Y and Vertein, D and Calubag, MF and Trautman, ME and Green, CL and Rigby, MJ and Puglielli, L and Lamming, DW},
title = {Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.06.27.600472},
pmid = {39005334},
issn = {2692-8205},
support = {F31 AG066311/AG/NIA NIH HHS/United States ; I01 BX004031/BX/BLRD VA/United States ; F31 AG082504/AG/NIA NIH HHS/United States ; R01 AG084156/AG/NIA NIH HHS/United States ; R01 AG062328/AG/NIA NIH HHS/United States ; F32 AG077916/AG/NIA NIH HHS/United States ; T32 AG000213/AG/NIA NIH HHS/United States ; RF1 AG056771/AG/NIA NIH HHS/United States ; R01 DK125859/DK/NIDDK NIH HHS/United States ; R01 AG078794/AG/NIA NIH HHS/United States ; U01 AG081482/AG/NIA NIH HHS/United States ; IS1 BX005524/BX/BLRD VA/United States ; F31 AG081115/AG/NIA NIH HHS/United States ; R01 GM148487/GM/NIGMS NIH HHS/United States ; R01 NS094154/NS/NINDS NIH HHS/United States ; },
abstract = {Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition, suggesting that the benefits of acarbose on AD are largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a Western diet.},
}

@article {pmid39005132,
year = {2024},
author = {Singh, S and Kushwaha, V and Sisodia, S and Kumar, S and Sahu, KK},
title = {Beta-Site APP-Cleaving Enzyme-1 Inhibitory Role of Natural Flavonoids in the Treatment of Alzheimer's Disease.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249315049240710063455},
pmid = {39005132},
issn = {1875-6166},
abstract = {Alzheimer's Disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive function, including memory loss, reasoning difficulties, and disorientation. Its hallmark features include the formation of neurofibrillary tangles and neuritic plaques in the brain, disrupting normal neuronal function. Neurofibrillary tangles, composed of phosphorylated tau protein and neuritic plaques, containing amyloid-β protein (Aβ) aggregates, contribute to the degenerative process. The discovery of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in 1999 revolutionized our understanding of AD pathogenesis. BACE1 plays a crucial role in the production of Aβ, the toxic protein implicated in AD progression. Elevated levels of BACE1 have been observed in AD brains and bodily fluids, underscoring its significance in disease onset and progression. Despite setbacks in clinical trials of BACE1 inhibitors due to efficacy and safety concerns, targeting BACE1 remains a promising therapeutic strategy for early-stage AD. Natural flavonoids have emerged as potential BACE1 inhibitors, demonstrating the ability to reduce Aβ production in neuronal cells and inhibit BACE1 activity. In our review, we delve into the pathophysiology of AD, highlighting the central role of BACE1 in Aβ production and disease progression. We explore the therapeutic potential of BACE1 inhibitors, including natural flavonoids, in controlling AD symptoms. Additionally, we provide insights into ongoing clinical trials and available patents in this field, shedding light on future directions for AD treatment research.},
}

@article {pmid39004678,
year = {2024},
author = {Bhat, SS and Kulkarni, SR and Uttarkar, A and Niranjan, V},
title = {Computational Insights into Papaveroline as an In Silico Drug Candidate for Alzheimer's Disease via Fyn Tyrosine Kinase Inhibition.},
journal = {Molecular biotechnology},
volume = {},
number = {},
pages = {},
pmid = {39004678},
issn = {1559-0305},
abstract = {Alzheimer's disease (AD) poses a significant global health challenge, necessitating the exploration of novel therapeutic strategies. Fyn Tyrosine Kinase has emerged as a key player in AD pathogenesis, making it an attractive target for drug development. This study focuses on investigating the potential of Papaveroline as a drug candidate for AD by targeting Fyn Tyrosine Kinase. The research employed high-throughput virtual screening and QSAR analysis were conducted to identify compounds with optimal drug-like properties, emphasizing adherence to ADMET parameters for further evaluation. Molecular dynamics simulations to analyze the binding interactions between Papaveroline and Staurosporine with Fyn Tyrosine Kinase over a 200-ns period. The study revealed detailed insights into the binding mechanisms and stability of the Papaveroline-Fyn complex, showcasing the compound's potential as an inhibitor of Fyn Tyrosine Kinase. Comparative analysis with natural compounds and a reference compound highlighted Papaveroline's unique characteristics and promising therapeutic implications for AD treatment. Overall, the findings underscore Papaveroline's potential as a valuable drug candidate for targeting Fyn Tyrosine Kinase in AD therapy, offering new avenues for drug discovery in neurodegenerative diseases. This study contributes to advancing our understanding of molecular interactions in AD pathogenesis and paves the way for further research and development in this critical area.},
}

@article {pmid39004381,
year = {2024},
author = {Althobaiti, NA and Al-Abbas, NS and Alsharif, I and Albalawi, AE and Almars, AI and Basabrain, AA and Jafer, A and Ellatif, SA and Bauthman, NM and Almohaimeed, HM and Soliman, MH},
title = {Gadd45A-mediated autophagy regulation and its impact on Alzheimer's disease pathogenesis: Deciphering the molecular Nexus.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167353},
doi = {10.1016/j.bbadis.2024.167353},
pmid = {39004381},
issn = {1879-260X},
abstract = {BACKGROUND: The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD).

METHODS: Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology.

RESULTS: Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A[-/-]) mice revealed that Gadd45A[-/-] mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A[-/-] mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A[-/-] mice, likely contributing to the observed cognitive deficits.

CONCLUSIONS: These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.},
}

@article {pmid39004063,
year = {2024},
author = {Yang, J and Zhao, H and Qu, S},
title = {Phytochemicals targeting mitophagy: Therapeutic opportunities and prospects for treating Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {177},
number = {},
pages = {117144},
doi = {10.1016/j.biopha.2024.117144},
pmid = {39004063},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder and the leading cause of age-related cognitive decline. Recent studies have established a close relationship between mitophagy and the pathogenesis of AD. Various phytochemicals have shown promising therapeutic effects in mitigating the onset and progression of AD. This review offers a comprehensive overview of the typical features of mitophagy and the underlying mechanisms leading to its occurrence in AD, highlighting its significance in the disease's pathogenesis and progression. Additionally, we examine the therapeutic mechanisms of synthetic drugs that induce mitophagy in AD. Finally, we summarize recent advances in research on phytochemicals that regulate mitophagy in the treatment of AD, potentially guiding the development of new anti-AD drugs.},
}

@article {pmid39004026,
year = {2024},
author = {Aslim, B and Nigdelioglu Dolanbay, S and Baran, SS},
title = {Exploring allocryptopine as a neuroprotective agent against oxidative stress-induced neural apoptosis via Akt/GSK-3β/tau pathway modulation.},
journal = {Computational biology and chemistry},
volume = {112},
number = {},
pages = {108144},
doi = {10.1016/j.compbiolchem.2024.108144},
pmid = {39004026},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is characterized by neuronal loss due to hyperphosphorylated proteins induced by oxidative stress. AD remains a formidable challenge in the medical field, as current treatments focusing on single biomarkers have yielded limited success. Hence, there's a burgeoning interest in investigating novel compounds that can target mechanisms, offering alternative therapeutic approaches. The aim of this study is to investigate the effects of allocryptopine, an isoquinoline alkaloid, on mechanisms related to AD in order to develop alternative treatment strategies. In this study, the in vitro AD cell model was obtained by inducing nerve growth factor (NGF)-differentiated PC12 (dPC12) cells to oxidative stress with H2O2, and also the effect mechanism of different allocryptopine concentrations on the in vitro AD cell model was studied. The treatments' antioxidative effects at the ROS level and their regulation of the cell cycle were assessed through flow cytometry, while their anti-apoptotic effects were evaluated using both flow cytometry and qRT-PCR. Additionally, the phosphorylation levels of Akt, GSK-3β, and tau proteins were analyzed via western blot, and the interactions between Akt, GSK-3β, CDK5 proteins, and allocryptopine were demonstrated through molecular docking. Our study's conclusive results revealed that allocryptopine effectively suppressed intracellular ROS levels, while simultaneously enhancing the Akt/GSK-3β signaling pathway by increasing p-Akt and p-GSK-3β proteins. This mechanism played a critical role in inhibiting neural cell apoptosis and preventing tau hyperphosphorylation. Moreover, allocryptopine demonstrated its ability to regulate the G1/S cell cycle progression, leading to cell cycle arrest in the G1 phase, and facilitating cellular repair mechanisms, potentially contributing to the suppression of neural apoptosis. The in silico results of allocryptopine were shown to docking with the cyclin-dependent kinase 5 (CDK 5) playing a role in tau phosphorylation Akt and GSK-3β from target proteins. Therefore, the in silico study results supported the in vitro results. The results showed that allocryptopine can protect dPC12 cells from oxidative stress-induced apoptosis and hyperphosphorylation of the tau protein by regulating the Akt/GSK-3β signaling pathway. Based on these findings, it can be suggested that allocryptopine, with its ability to target biomarkers and its significant effects on AD-associated mechanisms, holds promise as a potential candidate for drug development in the treatment of AD. Further research and clinical trials are recommended in the future.},
}

@article {pmid39003489,
year = {2024},
author = {Ayoup, MS and Ghanem, M and Abdel-Hamid, H and Abu-Serie, MM and Masoud, A and Ghareeb, DA and Hawsawi, MB and Sonousi, A and Kassab, AE},
title = {New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer's disease: design, synthesis, and biological evaluation.},
journal = {BMC chemistry},
volume = {18},
number = {1},
pages = {130},
pmid = {39003489},
issn = {2661-801X},
support = {GrantA440//King Faisal University/ ; },
abstract = {A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64-70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives' significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.},
}