Treatment Of Alzheimer's Disease Research Articles

Alzheimer's disease and gut-brain axis: Drosophila melanogaster as a model

Research indicates that by 2050, more than 150 million people will be living with Alzheimer's disease (AD), a condition associated with neurodegeneration due to the accumulation of amyloid-beta and tau proteins. In addition to genetic background, endocrine disruption, and cellular senescence, management of the gut microbiota has emerged as a key element in the diagnosis, progression, and treatment of AD, as certain bacterial metabolites can travel through the bloodstream and cross the blood-brain barrier. This mini-review explores the relationship between tau protein accumulation and gut dysbiosis in Drosophila melanogaster. This model facilitates the investigation of how gut-derived metabolites contribute to neurocognitive impairment and dementia. Understanding the role of direct and indirect bacterial by-products, such as lactate and acetate, in glial cell activation and tau protein dynamics may provide insights into the mechanisms of AD progression and contribute to more effective treatments. Here we discuss how the simplicity and extensive genetic tools of Drosophila make it a valuable model for studying these interactions and testing potential therapeutics, including probiotics. Integrating Drosophila studies with other established models may reveal conserved pathways and accelerate the translation of findings into clinical applications.

Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins.

Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimer's disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO and other chelators do enter the brain despite some contrary reports. Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid-β protein precursor (AβPP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice. Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and AβPP processing by western blot. DFO decreased brain iron 18% (p < 0.01) estimated by R2 MRI and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. AβPP and secretase enzymes also decreased by 30%. WT mice respond to DFO with decreased AβPP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered AβPP and secretase enzymes.

Xinnaoxin capsule alleviates neuropathological changes and cognitive deficits in Alzheimer's disease mouse model induced by D-galactose and aluminum chloride via reducing neuroinflammation and protecting synaptic proteins.

Originally formulated to mitigate high-altitude sickness, Xinnaoxin capsules (XNX) are composed of three traditional Chinese medicines (Rhodiola rosea L., Lycium barbarum L. and Hippophae rhamnoides) with properties of anti-hypoxia, anti-fatigue, and anti-aging. Emerging evidence now suggests that XNX may also offer therapeutic benefits in Alzheimer's disease (AD), highlighting its potential significance in the development of novel AD treatments. This study aims to investigate whether XNX improves AD-related behavioral and cognitive deficits by enhancing antioxidant defenses, reducing peripheral and neuroinflammation, and protecting neurons. The AD mouse model was established using D-galactose and aluminum chloride. Spatial memory and anxiety-like behaviors were assessed via the Morris water maze and open field tests to evaluate the therapeutic effects of XNX. Biochemical markers in hippocampal tissue and serum were measured using ELISA kits, while serum chemical composition was analyzed by LC-MS. Histopathological changes and amyloid-β deposition in the hippocampus were examined through hematoxylin-eosin (HE) staining and immunofluorescence. Additionally, hippocampal expression of apoptotic proteins Bax and Caspase-3, anti-apoptotic protein Bcl-2, and synaptic proteins PSD-95 and Syn were assessed via Western blot. Behavioral tests demonstrated that XNX significantly improved spatial learning and memory abilities, as well as reduced anxiety-like behaviors in AD mice. XNX also modulated inflammatory cytokines and oxidative stress markers in hippocampal tissue and serum, while reducing amyloid-β deposition. Further LC-MS analysis of serum revealed a marked upregulation of compounds such as adenosine following treatment, with key metabolic pathways affected, including linoleic acid metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis. HE staining and immunofluorescence indicated that XNX ameliorated neuronal damage and decreased amyloid-β accumulation. Western blot analysis confirmed that XNX inhibited neuronal apoptosis and preserved synaptic proteins in the hippocampus. XNX mitigates AD-induced behavioral and cognitive deficits by enhancing antioxidant defenses, reducing peripheral and neuroinflammation, and protecting neurons. Our findings provide valuable data and a theoretical foundation for the potential therapeutic application of XNX in AD treatment and its further development.

Natural Compounds for Alzheimer's Prevention and Treatment: Integrating Selformer-Based Computational Screening with Experimental Validation

BackgroundThis study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict natural compounds (NCs) with potential in Alzheimer's disease (AD) treatment. The NCs were identified based on activity related to seven AD-specific genes, including acetylcholinesterase (AChE), amyloid precursor protein (APP), beta-secretase 1 (BACE1), and presenilin-1 (PSEN1). MethodsWe implemented a computational pipeline using SELFormer and deep learning techniques, conducted optimal clustering and quantitative structure-activity relationship (QSAR) analyses, and performed a uniform manifold approximation and projection (UMAP) to categorize compounds based on bioactivity levels. Molecular docking analysis was carried out on selected compounds. To validate the computational predictions, we conducted in vitro studies using nerve growth factor (NGF)-differentiated PC12 cells. Finally, we mapped the relationships between food sources containing the identified compounds and their target proteins. ResultsOptimal clustering analysis revealed five distinct groups of NCs, while QSAR analysis highlighted variations in molecular properties across clusters. The UMAP projection identified 17 highly active NCs (pIC50>7). Molecular docking analysis showed that cowanin, β-caryophyllene, and L-citronellol demonstrated decreased binding energy across target proteins. In vitro studies confirmed significant biological activities of these compounds, including increased cell viability, decreased AChE activity, reduced lipid peroxidation and tumor necrosis factor (TNF)-α mRNA expression, and increased brain-derived neurotrophic factor (BDNF) mRNA expression compared to the control. The study also identified natural sources of these compounds, such as anatidae, mangosteen, and celery, providing insights into potential dietary interventions. ConclusionThis integrated computational and experimental approach offers a promising framework for identifying potential NCs for AD treatment. The results contribute to exploring effective therapeutic strategies against AD.

Design, synthesis, and evaluation of novel benzofuran and pyrazole-based derivatives as dual AChE/BuChE inhibitors with antioxidant properties for Alzheimer's disease management.

As a complicated neurodegenerative disorder with several clinical hallmarks, Alzheimer's disease (AD) requires multi-target treatment medicines to address multiple elements of disease progression. In this study, we reported two novel series of compounds: benzofuran-based donepezil analogs (9a-i) and their pyrazole-based counterparts (11a-i) as potential dual inhibitors of AChE and BuChE with additional antioxidant properties, aiming to address multiple pathological aspects of AD simultaneously. The design strategy employed bioisosteric replacement, substituting donepezil's indanone motif with a benzofuran ring in series (9a-i) to maintain crucial hydrogen bonding interactions with the Phe295 residue in the enzyme's active site. Subsequently, the benzofuran ring underwent cleavage, yielding pyrazole-tethered hydroxyphenyl derivatives (11a-i). The biological evaluation revealed that benzofuran-based derivative 9g exhibited exceptional efficacy against both AChE and BuChE, with IC50 values of 0.39 and 0.51μg/ml, respectively, although it lacked antioxidant activity. Compound 11f demonstrated dual inhibition of AChE (IC50=1.24μg/ml) and BuChE (IC50=1.85μg/ml) while also displaying strong DPPH free radical scavenging activity (IC50=3.15μg/ml). In vivo toxicity studies on compound 11f revealed a favorable safety profile, with no signs of toxicity or adverse events in acute oral toxicity tests in male Wistar rats. Chronic administration of 11f resulted in negligible differences in blood profiles, hepatic enzymes, urea, creatinine, and albumin levels compared to the control group. Histopathological examination of hepatic and kidney tissues from treated rats showed normal histology without damage. In silico molecular docking analysis was performed to rationalize the design approaches and support the experimental findings. This study provides valuable insights into the development of multi-target compounds for potential Alzheimer's disease treatment.

Biofilm-modified Prussian blue improves memory function in late-stage Alzheimer's disease mice with triple therapy.

Alzheimer's disease (AD) is a neurodegenerative disease that is significantly characterized by cognitive and memory impairments, which worsen significantly with age. In the late stages of AD, metal ion disorders and an imbalance of reactive oxygen species (ROS) levels occur in the brain microenvironment, which causes abnormal aggregation of β-amyloid (Aβ), leading to a significant worsening of the AD symptoms. Therefore, we designed a composite nanomaterial of macrophage membranes-encapsulated Prussian blue nanoparticles (PB NPs/MM). Prussian blue nanoparticles (PB NPs) are capable of chelating Cu2+ and reducing ROS. Macrophage membranes (MM) have advantages over liposomal and erythrocyte membrane carriers, including inflammatory targeting capabilities and more effective immune evasion. Concurrently, the excellent photothermal ability of PB NPs can briefly open the blood-brain barrier (BBB) under near-infrared laser irradiation, which improves the transport efficiency of PB NPs/MM across the BBB and ablates Aβ deposition, thus achieving optimal therapeutic efficacy. In vitro experiments demonstrated that PB NPs/MM is a multifunctional nanosystem, which can effectively inhibit Cu2+-induced Aβ monomers aggregation, photothermally depolymerize Aβ fibrils, and attenuate oxidative stress through the combined treatment of chelating metals, photothermal therapy and scavenging ROS. In behavioral experiments, it also significantly improved the cognitive and learning deficits in late-stage APP/PS1 mice, thereby providing new ideas for the treatment of late-stage AD and other neurodegenerative diseases.

Identifying proteomic prognostic markers for Alzheimer's disease with survival machine learning: The Framingham Heart Study.

Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations. Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9 % women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in a separate group of 430 participants younger than 55 years (mean age 46, 56.7 % women). Over a mean follow-up of 20 years, 132 (15.4 %) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4 + status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4 + status across 15-25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in the 339 participants (beta = -0.061, P = 0.046), 430 participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003). These findings highlight the utility of machine learning method in identifying proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.

Discovery of novel bicyclic and tricyclic cyclohepta[b]thiophene derivatives as multipotent AChE and BChE inhibitors, in-Vivo and in-Vitro assays, ADMET and molecular docking simulation.

Alzheimer's disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-β deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[b]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD. All synthesized compounds exhibited AChE inhibition with IC50 values below 15μM, while all compounds exhibited BChE inhibition with IC50 values below 25μM. Compounds 9 and 12 exhibited AChE inhibitory activities with IC50 values of 0.51μM and 0.55μM, respectively. Compounds 5 and 9 demonstrated excellent inhibitory activity against BChE with IC50 values of 2.9μM and 2.48μM, respectively. Compounds 9, 13, and 14 were found to be the most active in terms of the decrease in the escape latency time, with values comparable to that of Donepezil. Compounds 10, 11, and 12 exhibited promising effects on learning and memory. Compounds 5, 10, 11, and 12 exhibited promising SAP values of 70.67%, 71.5%, 74.33% and 73.83%, respectively. Other biomarkers were evaluated in rat brains including TAC, MDA, SOD, BDNF, IL-β and TNF-α. Fundamental features of ADMET have been computed in-silico for synthesized compounds. Molecular docking was performed to confirm the binding of the novel compounds to the targets.

Advancing Alzheimer's disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models.

Exposure to chronic stress and high levels of glucocorticoid hormones in adulthood has been associated with cognitive deficits and increased risk of Alzheimer's disease (AD). Dazucorilant has recently emerged as a selective glucocorticoid receptor (NR3C1) modulator, exhibiting efficacy in counteracting amyloid-β toxicity in an acute model of AD. We aim to assess the therapeutic potential of dazucorilant in reversing amyloid and tau pathologies through the inhibition of glucocorticoid receptor pathological activity, and providing additional evidence for its consideration in AD treatment. The efficacy of dazucorilant was evaluated in two transgenic mouse models of amyloid pathology. The slowly progressing J20 and the aggressively pathological 5xFAD mice. Behavioural analysis was conducted to evaluate welfare, cognitive performances and anxiety levels. The activity of the glucocorticoid receptor system, neuroinflammation, amyloid burden and tau phosphorylation were examined in hippocampi. In both AD models, chronic treatment with dazucorilant improved working and long-term spatial memories along with the inhibition of glucocorticoid receptor-dependent pathogenic processes and the normalization of plasma glucocorticoid levels. Dazucorilant treatment also resulted in a reduction in tau hyperphosphorylation and amyloid production and aggregation. Additionally, dazucorilant seemed to mediate a specific re-localization of activated glial cells onto amyloid plaques in J20 mice, suggesting a restoration of physiological neuroinflammatory processes. Dazucorilant exhibited sustained disease-modifying effects in two AD models. Given that this compound has demonstrated safety and tolerability in human subjects, our results provide pre-clinical support for conducting clinical trials to evaluate its potential in AD.

Identification of therapeutic targets for Alzheimer’s Disease Treatment using bioinformatics and machine learning

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that currently lacks effective treatment options. This study aimed to identify potential therapeutic targets for the treatment of AD using comprehensive bioinformatics methods and machine learning algorithms. By integrating differential gene expression analysis, weighted gene co-expression network analysis, Mfuzz clustering, single-cell RNA sequencing, and machine learning algorithms including LASSO regression, SVM-RFE, and random forest, five hub genes related to AD, including PLCB1, NDUFAB1, KRAS, ATP2A2, and CALM3 were identified. PLCB1, in particular, exhibited the highest diagnostic value in AD and showed significant correlation with Braak stages and neuronal expression. Furthermore, Noscapine, PX-316, and TAK-901 were selected as potential therapeutic drugs for AD based on PLCB1. This research provides a comprehensive and reliable method for the discovery of AD therapeutic targets and the construction of diagnostic models, offering important insights and directions for future AD treatment strategies and drug development.

APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease

The ApoE ε4 allele (APOEε4) is a major genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to demyelination and cognitive decline. However, its effects on the lipid transporters apolipoprotein E (ApoE) and fatty acid-binding protein 7 (Fabp7), which are crucial for the maintenance of myelin in white matter (WM) during the progression of AD remain underexplored. To evaluate the effects of APOEε4 on ApoE, Fabp7 and myelin in the WM of the frontal cortex (FC), we examined individuals carrying one ε4 allele that came to autopsy with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and mild to moderate AD compared with non-carrier counterparts. ApoE, Fabp7 and Olig2 immunostaining was used to visualize cells, whereas myelin basic protein (MBP) immunocytochemistry and luxol fast blue (LFB) histochemistry of myelin in the WM of the FC were combined with quantitative morphometry. We observed increased numbers of ApoE-positive astrocytes in the WM of both NCI and MCI APOEε4 carriers compared with non-carriers, whereas Fabp7-positive cells were elevated only in AD. Conversely, Olig2 cell counts and MBP immunostaining decreased in MCI APOEε4 carriers compared to non-carriers, while LFB levels were higher in NCI APOEε4 carriers compared to non-carriers. Although no correlations were found between ApoE, Fabp7, and cognitive status, LFB measurements were positively correlated with perceptual speed, global cognition, and visuospatial scores in APOEε4 carriers across clinical groups. The present findings suggest that the ε4 allele compromises FC myelin homeostasis by disrupting the lipid transporters ApoE, Fabp7 and myelination early in the onset of AD. These data support targeting cellular components related to WM integrity as possible treatments for AD.

Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction.

Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP display altered blood flow regulation at rest and during neurovascular coupling, defects in mural cell activity, and an abnormal vascular sex-dependent response to Aβ. Antagonizing endothelin-1 receptor A signaling partly rescues the vascular impairments, but only in male mice. Treatment of CD2AP mutant mice with reelin glycoprotein that mitigates the effects of CD2AP loss function via ApoER2 increases resting cerebral blood flow and even protects male mice against the noxious effect of Aβ. Thus, endothelial CD2AP plays critical roles in cerebrovascular functions and represents a novel target for sex-specific treatment in AD.

Polymers for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is one of the most common diseases of the central nervous system in the middle-aged and elderly population. It is a neurodegenerative disorder, and its main clinical symptoms include the loss of established memories, a decline in learning capacity, and the buildup of β-amyloid peptides. The disease is often accompanied by neurodegenerative changes and the formation of neurofibrillary tangles. However, the number of drugs available for the clinical treatment of AD remains limited. Currently, existing medications are not effective in completely curing the disease or stopping its progression. Due to their excellent biocompatibility and biodegradability, polymers have been widely used as drug delivery carriers in various fields including cancer therapy and wound healing. The use of polymers enables targeted drug delivery and prolonged release profiles. In recent years, researchers have made significant progress in utilizing polymers such as polyethylene glycol, poly (lactic-co-glycolic acid) (PLGA), and chitosan (CS) to deliver drugs and blood-brain barrier receptor ligands for the treatment of AD. Moreover, many polymers with inherent therapeutic properties have been developed, including the already marketed GV-971 as well as experimental polymers such as PLGA and CS oligosaccharide. This review summarizes the applications of polymers in AD treatment over the past few years and highlights their current limitations to help researchers better understand current advancements in polymer development and identify future research directions.

Melatonin Overexpression in the Management of Alzheimer's Disease: Therapeutic Exploration.

Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by the accumulation of neurofibrillary tangles and β-amyloid plaques, leading to a decline in cognitive function. AD is characterized by tau protein hyperphosphorylation and extracellular β-amyloid accumulation. Even after much research, there are still no proven cures for AD. The neuroprotective, anti-inflammatory, and antioxidant qualities of melatonin, a hormone mostly produced by the pineal gland, have drawn interest as a possible treatment option for AD. This study looks at new evidence that suggests melatonin overexpression to be a promising therapy option for AD. Melatonin levels naturally decline with age and decrease more significantly in individuals with AD, worsening neurodegenerative processes. Melatonin has therapeutic potential as it inhibits Aβ formation, prevents amyloid fibril extension through structure-dependent interactions, and protects neurons from Aβ-induced toxicity. Melatonin promotes neurogenesis, which is decreased in AD, suggesting it may treat the disease's many pathologies. The review emphasizes the importance of melatonin's mechanisms of action, including its capacity to reduce neuroinflammation, regulate mitochondrial function, scavenge free radicals, and influence apoptotic pathways. As research into AD continues, this article provides a forward-looking perspective on how future studies could leverage melatonin's multifaceted neuroprotective properties to develop more effective treatments for AD.

Noradrenergic system in the pathogenesis of age-dependent neurodegeneration

Ageing is a key factor in the development of cognitive decline and neurodegeneration, including Alzheimer’s disease (AD), the most common form of dementia diagnosed. In 2023 the US Federal Drug Administration (FDA) approved a new drug (Lecanemab, Leqembi) to treat AD that very moderately slows down cognitive decline in early-stage AD (van Dyck et al., 2023). Donanemab (Kisunla, Eli Lilley), acting similarly to lecanemab, was approved by the FDA in 2024 in the US, but not yet by the European Medicines Agency (EMA) in the EU. The mechanism of action of both of these monoclonal antibodies is similar to that of aducanumab (Aduhelm), conditionally approved for AD in 2021 (but subsequently discontinued by the producer), by acting on and reducing β-amyloid deposits (Sevigny et al., 2016; van Dyck et al., 2023). However, trials of all these monoclonal antibodies revealed significant adverse events (brain swelling or brain bleeding); hence treatment for AD and neurodegeneration in general remains an important unmet medical need, affecting millions of people worldwide. Here I discuss the role of the noradrenergic system innervating the brain and the spinal cord, consisting of the nucleus locus coeruleus (LC), which appears to be the most vulnerable structure in the central nervous system (CNS) to ageing-related factors, leading to early LC demise and cognitive impairments. Therefore, I propose that understanding the action of noradrenaline on the brain cells, in particular on astrocytes, homeostasis-providing cells, which exhibit a high density of adrenergic receptors, is a future strategy to develop new drugs to mitigate neurodegeneration and cognitive decline. Keywords: ageing; noradrenaline; adrenoceptors; locus coeruleus; neurodegeneration, neuroglia, astrocytes

Di Huang Yi Zhi Fang improves cognitive function in APP/PS1 mice by inducing neuronal mitochondrial autophagy through the PINK1-parkin pathway.

Alzheimer's disease (AD) is an irreversible age-related neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Di Huang Yi Zhi (DHYZ) formula, a traditional Chinese herbal compound comprising several prescriptions, demonstrates properties that improve cognitive abilities in clinical. Nonetheless, its molecular mechanisms on treating AD through improving neuron cells mitochondria function have not been deeply investigated. This study administered DHYZ to APP/PS1 mice to explore its potential therapeutic mechanisms in AD treatment. APP/PS1 transgenic mice were given DHYZ (L, M, H), donepezil, or distilled water for a consecutive 12-week period. The Morris water maze test was used to assess memory capacity, transmission electron microscopy was used to observe mitochondrial and synaptic structures, immunohistochemistry and western blot detected proteins involved in the mitochondrial autophagy pathway, ELISA measured serum Aβ content, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assessed neuronal cell apoptosis. DHYZ demonstrates a notable therapeutic impact on mice with AD, effectively improving cognitive and memory impairments. DHYZ decreases Aβ accumulation in the hippocampus by reducing BACE1 activity and enhancing Aβ clearance through the blood-brain barrier. Additionally, DHYZ significantly suppresses neuronal apoptosis, enhances synaptic structure, and increases synapse numbers, processes strongly linked to the activation of mitochondrial PINK1-Parkin autophagy. DHYZ enhances cognitive function in APP/PS1 mice by stimulating neuronal mitochondrial autophagy through the PINK1-Parkin pathway.

Trafficking of Muscarinic 1 Acetylcholine Receptor Regulated by VPS35 in Alzheimer's Disease.

Muscarinic 1 acetylcholine receptor (M1AChR) is a member of the Gprotein- coupled receptor superfamily, with the dysfunction being linked to the onset of Alzheimer's Disease (AD). Retromer complex with Vacuolar Protein Sorting-35 (VPS35) as the core plays an important role in the transport of biological proteins and has been confirmed to be closely related to the pathogenesis of AD. This study was designed to determine whether VPS35 could affect the trafficking mechanism of M1AChRs. The interaction between VPS35 and M1AChR was studied by co-immunoprecipitation method, and the recycling of M1AChR influence by VPS35 was analyzed using biotinylation technology. It was found that VPS35 affected the localization of M1AChR on the cell membrane by regulating intracellular M1AChR transport, thus controlling the M1AChR-mediated cholinergic signaling pathway. The findings presented here provide a potential pathogenesis and pathway for the treatment of AD.

Inhibition of amyloid-beta aggregation by phenyl butyric acid analogs and bile acids: a comprehensive in silico study.

Alzheimer's disease (AD) is a degenerative neurological disorder defined by the formation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Current pharmacological treatments for AD only provide symptomatic relief, and there is a lack of definitive disease-modifying therapies. Chemical chaperones, such as 4-Phenylbutyric acid (4PBA) and Tauroursodeoxycholic acid, have shown neuroprotective effects in animal and cell culture models. However, their therapeutic application is limited due to low bioavailability and poor ability to cross the blood-brain barrier. The study aims to design and identify novel derivatives of 4PBA analogs & bile acids using computational molecular docking, ADME/pharmacokinetic predictions, and molecular dynamic (MD) simulations to develop potential anti-aggregation compounds targeting Aβ, a key player in AD pathology. A comprehensive library of 25,802 derivatives was created using 3PPA, 3MPP, 5PVA, IPA, and bile acid scaffolds, which were examined for their pharmacokinetic characteristics and binding affinities with the Aβ protein. Molecular docking and ADME predictions revealed IPA-1 and DCA-1 as leading candidates due to their robust binding interactions with the Aβ protein, along with minimal toxicity, high solubility, and good absorption profiles. Further, MD analysis over an extended period at 100ns confirmed the better stability of IPA-1 and DCA-1 during interaction with the protein. These findings highlight promising drug candidates, necessitating further validation through cell and animal studies.

The Effect of Physical Activity on Alzheimer’s Disease - Systematic Review

Dementia, particularly Alzheimer's disease (AD), is a growing global health concern, with an estimated 50 million people affected worldwide. The prevalence of AD is projected to increase significantly with aging populations. Despite the absence of a cure, early intervention during the prodromal phase can slow the progression of AD, highlighting the importance of identifying modifiable risk and protective factors. Physical inactivity is one of the leading modifiable risk factors, contributing to approximately 40% of dementia cases. This review explores the role of physical exercise, particularly resistance training (RET), aerobic exercises, and dance movement interventions (DMI), as therapeutic approaches for AD prevention and treatment. Evidence suggests that regular physical activity enhances cognitive function, reduces neuroinflammation, improves brain structure, and supports neuroplasticity. Both RET and aerobic exercise have been shown to delay the onset of cognitive decline, with RET also reducing amyloid plaque formation and promoting neuroprotection. DMI further benefits individuals with AD by improving cognitive function, mood regulation, social interaction, and physical coordination. Additionally, the review examines the relationship between obesity and AD. Although obesity is traditionally seen as a risk factor for cognitive decline, recent studies suggest that obesity in late life may have protective effects, potentially due to factors like lower amyloid-beta levels and larger hippocampal volume. This review emphasizes the importance of physical exercise and its potential to mitigate cognitive decline and improve quality of life in individuals at risk of or living with Alzheimer’s disease.

Protocatechuic Acid Improves Alzheimer's Disease by Regulating the Cholinergic Synaptic Signaling Pathway.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by memory decline and cognitive impairments. The clinical treatments for AD have numerous adverse effects; hence, the exploration of natural products for AD therapy is of significant importance. Protocatechuic acid (PA), a natural phenolic acid, has been shown to possess various pharmacological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the mechanisms underlying its therapeutic potential for AD remain elusive. This study utilized a β-amyloid (Aβ) injection into the hippocampus of mice as an AD model and L-glu-induced HT-22 cell neurotoxicity and lipopolysaccharides (LPS)-induced cellular neuroinflammation models to assess reactive oxygen species (ROS), JC-1, and relevant biochemical markers. This study examined behavioral, pathological, and inflammatory factors and investigated the molecular mechanisms through transcriptomics, western blot, and molecular docking studies. This study's findings reveal that high-dose PA (50mg/kg) improves symptoms in AD mice through the cholinergic synaptic signaling pathway. This study indicates that PA is a potential candidate for AD treatment targeting the cholinergic synaptic signaling pathway, providing a lead compound for AD therapy.