📋 Browse Articles

β-amyloid (Aβ) inhibition significantly attenuates the early-stage Alzheimer's disease (AD) progression, but the improvement in cognitive function remains limited by neuroinflammation. Here, we developed a bioinspired neuroenhancer that concurrently targets both Aβ aggregation and neuroinflammation. Rutin and small interfering RNA targeting beta-site amyloid precursor protein cleaving enzyme 1 (siBACE1) were co-loaded into the calcium phosphate core, which was further coated with lipid bilayers and Angiopep-2/rabies virus glycoprotein 29 peptides to form the multifunctional neuroenhancer (RB@LCP-AR). RB@LCP-AR not only releases siBACE1 to silence BACE1 expression and block Aβ production from the cleavage of amyloid precursor protein, but also releases Rutin to suppress the Aβ aggregation. Moreover, the released Rutin of RB@LCP-AR directly alleviates Aβ-induced mitochondria dysfunction and intracellular ROS production in neuronal cells. Notably, the targeting of RB@LCP-AR to neurons and the inhibition of Aβ reduce the microgliosis and astrogliosis, further alleviating neuroinflammation and synapse loss. Consequently, AD mice receiving RB@LCP-AR treatment efficiently recovered their memory and cognition. Our study thus provides a coordinated targeting of Aβ and neuroinflammation inhibition, holding considerable potential to promote the recovery of memory and cognition in AD. Show less

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) and phosphorylated tau in the brain. It is reported that arctigenin (ATG) reduces the level of the enzyme 1 that cleaves β-site amyloid precursor protein and increases Aβ clearance by enhancing autophagy. Compound ARC-18 is a derivative of ATG. The main objective of this study is to investigate whether ARC-18 could improve cognitive function and disease progression by promoting autophagy in Alzheimer-like animal models. Three-month-old 5 × FAD mice were orally treated with the drug for three consecutive months. Water maze and novel object recognition were used to assess cognitive abilities of 5 × FAD mice. In the hippocampus of the mice' brain, APP processing-related proteins (sAPP Show less

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder with progression leading to a decline in cognition. Despite the extensive research, conventional therapies have limited activity and often cause side effects. This demands the need for novel, safer, and effective treatment of AD.ObjectiveThe objective of this study was to determine the phytochemical constituents and determine the anti-Alzheimer's activity of Show less

Aging is a "multidimensional engine" of biological dysfunction that can fundamentally reshape the pathology of Alzheimer's disease (AD), This review systematically elaborates on how aging synergistically promotes the core pathologies of AD: aging upregulates the activity of β-secretase 1 (BACE1)/γ-secretase, impairs the clearance function of glial cells and meningeal lymphatic drainage, and accelerates Aβ deposition; the imbalance of kinases/phosphatases, dysfunction of molecular chaperones, and aging exosome-mediated propagation of Tau "seeds" facilitate Tau pathology; hyperreactivity of microglia and the transformation of astrocytes to the A1 phenotype form a senescence-associated secretory phenotype (SASP) → neuroinflammation vicious cycle; downregulation of synaptic proteins and disintegration of the default mode network lead to cognitive decline. Recent studies have identified that the impaired transition of aging microglia to the disease-associated microglia (DAM) phenotype, peripheral-central aging signal transmission loops (the gut-brain axis, immune-brain axis, and metabolic-brain axis), as well as circadian rhythm/vascular metabolic dysregulation, have emerged as novel intervention targets. Precision strategies targeting aging mechanisms-such as senescent cell clearance, SASP inhibition, epigenetic reprogramming, and biomarker-guided early intervention-provide a new paradigm for blocking the progression of AD. Show less

Aluminum toxicity in rodents is well documented to be used for inducing experimental models that mimic the clinical phenotypes of Alzheimer's disease (AD). Liraglutide is a well-known antidiabetic drug promising for modulating neurodegenerative conditions. Thus, investigating the ameliorative effects of Liraglutide on AD induced by aluminum chloride (AlCl Show less

Single Particle Tracking (SPT) is a powerful technique for elucidating the dynamic behaviours of macromolecules within live cells. However, SPT's application to subcellular environments is hampered by the error-proneness of tracking at high particle velocities and densities and the lack of tools to assess trajectory reliability. Here, we introduce FidlTrack, a methodology that benchmarks and improves SPT fidelity. It contains three modules: a parameter optimiser that uses synthetic ground truth SPT data to determine the fidelity-maximising experimental and tracking settings; Structure-aware tracking, that exploits the information provided by organelle structures to constrain particle tracking algorithms; And a tracking quality evaluator that detects, quantifies and removes error-prone ambiguous track segments. Together these tools allow the rational design of SPT experiments, resolving the motion in tight and convoluted organelles, and provide up to 2-fold enrichment in accurate data. We showcase FidlTrack's utility for reliably tracking proteins in the cytosol, mitochondria and endoplasmic reticulum (ER). Further, we demonstrate its efficacy by analysing ER protein dynamics at exit sites, resolving BACE1 amyloidogenic cleavage of the amyloid precursor protein and characterising the spatiotemporal binding dynamics of an ER-targeted intrabody. FidlTrack is provided as a universal open-access platform that can be incorporated into any SPT pipeline. Show less

Diabetes is a major risk factor for diabetic encephalopathy (DE), which is closely associated with sporadic Alzheimer's disease. Folic acid (FA) receptor signaling can suppress generation of neuropathogenic amyloid-beta (Aβ) induced by high extracellular glucose, suggesting that enhanced activation of this pathway could be a therapeutic strategy against DE-associated dementia, but the precise molecular signaling mechanisms are unclear. We report that high glucose levels increased the expression of amyloid precursor protein (APP) and β-secretase (BACE1) in cultured neurons and concomitantly induced amyloidogenesis, while FA treatment suppressed high glucose-stimulated expression of APP and BACE1, Aβ release, and accumulation of mitochondrial reactive oxygen species. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was minimal under high glucose conditions, but was significantly upregulated together with downstream antioxidant enzymes following FA co-treatment. High glucose stimulation also increased folate receptor 1 (FOLR1) mRNA expression, suggesting a compensatory protective response. While treatment with 5-methyltetrahydrofolate (5-MTHF), the activated form of folate, did not significantly alter high glucose-induced upregulation of APP and BACE1, knockdown of FOLR1 mRNA reduced high glucose-stimulated Nrf2 expression and further augmented APP and BACE1 expression under high glucose conditions. Treatment with the STAT3 inhibitor 5'15-DPP also abolished high glucose-stimulated Nrf2 expression and increased APP and BACE1 expression levels. These findings indicate that FA/FOLR1 activation suppresses high glucose-induced amyloidogenesis by mitigating mitochondrial oxidative stress via STAT3/Nrf2 pathway signaling. In conclusion, present study suggests that the FA/FOLR1/STAT3/Nrf2 pathway is an effective therapeutic target for DE. Show less

Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC Show less

The discovery of dual acetylcholinesterase (AChE) and β-secretase (BACE1) inhibitors remains a promising strategy against multifactorial Alzheimer's disease. Here, rigorously curated ChEMBL-derived data were used to develop explainable QSAR (Quantitative structure-activity relationship) models for dual-inhibition prioritization. Molecules were standardized, near-duplicates were removed using a Tanimoto similarity threshold (≥ 0.80), and physicochemical outliers were filtered prior to modeling. Multiple classifiers (including Light Gradient-Boosting Machine, eXtreme Gradient Boosting, Random Forest, Support Vector Machine, k-Nearest Neighbors and Gradient Boosting Decision Trees) and fingerprints (e.g., RDKit fingerprints, Extended Connectivity Fingerprint) were benchmarked under scaffold-based nested cross-validation to prevent data leakage. Class imbalance was handled with SMOTETomek applied strictly within training folds. Model selection relied on F-Score, Area Under the Precision-Recall Curve, Matthews Correlation Coefficient (MCC), and Recall, and performance was accompanied by bootstrap confidence intervals, calibration curves, and Y-randomization controls. In classification, the top model (GBDT + ECFP6) achieved strong generalization (Recall ≈ 1.00, PR-AUC ≈ 0.84, MCC ≈ 0.81, F1 Score ≈ 0.84). Shapley Additive Explanations (SHAP) analysis highlighted aromatic and hydrogen-bonding substructures as key positive contributors. Prospective candidates (e.g., CHEMBL5082250, CHEMBL1651126, CHEMBL1651127) were evaluated by active-site-focused docking against AChE (PDB: 4EY7) and BACE1 (PDB: 2G94) with essential waters retained; docking scores (ΔG, kcal·mol⁻ Show less

A classical one-drug-one-target approach is ineffective against diseases with a multi-factorial pathogenesis, such as Alzheimer's disease (AD). On the other hand, multitarget approaches can provide a higher level of pharmacological interference which can better affect the disease network. Acetylcholinesterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE-1), glycogen synthase kinase 3 beta (GSK-3β), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), and phosphodiesterases (PDEs) are the main major targets of this network whose connection are still far from being fully understood. Aware of this limitation, we herein focus on the main chemotypes employed for AChE/BACE-1 targeting. These include mostly bioactive compounds based on chalcones, triazines, triazoles, piperidines, and flavonoids. Show less

A series of novel granatane-triazole hybrid molecules was designed, synthesized, and evaluated as dual acetylcholinesterase (AChE) and β-secretase 1 (BACE1) inhibitors. The compounds were obtained through a convergent synthetic route involving azide formation, triazole construction via dipolar cycloaddition, and final coupling with a granatane scaffold to give a pseudopelletierine (3-granatanone) analogue. In vitro assays demonstrated that all target compounds inhibited both AChE and BACE1. Molecular docking and molecular dynamics simulations revealed stable interactions with key catalytic residues, suggesting distinct binding modes compared to reference ligands. QSAR-based pharmacokinetic predictions indicated favorable blood-brain barrier permeability and compliance with key drug-likeness filters. These findings identify granatane-triazole hybrids as promising multi-target directed ligand (MTDL) candidates with potential for further optimization in the search for new anti-Alzheimer therapeutics. Show less

Autosomal dominant Alzheimer's disease (ADAD) serves as a model for presymptomatic biomarker discovery. Characterising the temporal profile of plasma biomarker levels in presymptomatic individuals may enhance understanding of disease pathogenesis, inform future clinical trials, and guide clinical interpretation. We evaluated 124 proteins using a NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in 270 plasma samples from a longitudinal cohort study of ADAD, comprising 113 individuals (73 mutation carriers and 40 non-carriers). We determined the plasma proteomic changes that distinguished mutation carriers from non-carriers. We then used predicted age at symptom onset to determine the approximate timing of presymptomatic divergence in biomarker levels in carriers relative to non-carriers. Nine proteins (Aβ42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed Aβ42 levels were elevated in carriers at least 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at 21-24 years before expected symptoms, total-tau at 19 years, GFAP and BACE1 at 14 years, and NfL at 6 years. Differences in AChE were seen in symptomatic individuals, likely reflecting cholinesterase inhibitor use. Multiple plasma proteins are elevated in presymptomatic and symptomatic autosomal dominant AD mutation carriers relative to non-carriers. Changes in eight biomarkers occur sequentially from 26 to 6 years prior to symptom onset. Combining biomarkers may help in staging presymptomatic AD and optimise clinical trial inclusion. Further work is needed to assess how these findings generalise to non-monogenic AD. The molecular pathology of Alzheimer's disease develops many years before the onset of symptoms, and multiple plasma biomarkers of Alzheimer's pathology have been identified. Understanding the timing of biomarker abnormality is important to guide trial design for the timing of interventions to prevent the onset of dementia. Using an autosomal dominant Alzheimer's disease cohort, we identify multiple plasma biomarkers that distinguish mutation carriers from non-carrier familial controls and characterise the timing of these changes relative to symptom onset. We demonstrate that biomarkers show change many years before symptom onset: markers of abnormal tau phosphorylation more than 20 years prior, followed by markers of reactive astrocytosis and synaptic dysfunction approximately 15 years prior, and neurodegenerative markers within 10 years of symptoms. Plasma biomarkers could be used in pre-clinical autosomal dominant Alzheimer's disease to chart disease trajectories and predict symptom onset, allowing targeted disease-modifying therapy implementation and optimised clinical trial design. Show less

Alzheimer's disease (AD) is the most prevalent cause of dementia, accounting for 60-80% of all cases and characterized by amyloid beta (Aβ) plaques and tau protein hyperphosphorylation. Among the signaling mechanisms implicated in AD, protein kinase C (PKC) isoforms and neuron-specific embryonic lethal abnormal vision-4 (ELAV4) have gained increasing attention due to their roles in synaptic plasticity, neuroinflammation, and mRNA stability. This review discusses the potential for targeting the PKC-ELAV4 axis to manage dementia. PKC isoforms, including PKC α, δ, and ε, are involved in amyloid-beta (Aβ) processing, tau phosphorylation, and regulation of mitochondrial activities, whereas ELAV4 stabilizes mRNAs that participate in both the degradation of Aβ (e.g., neprilysin) and the synthesis of Aβ (e.g., beta-site amyloid precursor protein cleaving enzyme 1, BACE1). We reviewed 75 papers published over the last 15 years using search terms such as neuroinflammation, synaptic plasticity, mRNA stability in dementia, ELAV, ELAV4, PKC, and PKC isoforms in databases including PubMed, WOS, and Google Scholar. Results were summarized, compared, and research gaps were identified during data collection and interpretation. ELAV4 can influence the processing of amyloid precursor protein (APP), the precursor of the amyloid-beta peptide, a hallmark of AD. Decreased expression of ELAV4 in the hippocampus is associated with dementia. PKC-δ activates c-Jun N-terminal kinase (JNK) expression, releases Beclin-1 from the Bcl2/Beclin-1 complex, and promotes autophagy. Oxidative stress and PKC η regulate the mitogenactivated protein kinase (MAPK) pathway, leading to tau phosphorylation and neuronal death. PKCε activators and ELAV4 inhibitors have positive effects on cognitive function and dementia management by inhibiting neuroinflammation and neuronal apoptosis, while PKC α, β, δ inhibitors may aid in managing different forms of dementia. This review highlights research gaps and proposes future directions for targeting the PKC-ELAV4 axis as a novel strategy in dementia management. Show less

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and is also responsible for more than half of all dementia cases. In our ongoing efforts to identify promising phytocompounds as potential modulators of AD-related molecular targets, we studied 53 phytocompounds from Bergenia ciliata, a medicinal plant known for its in vivo anti-Alzheimer activity. Acetylcholinesterase (AChE), GSK-3β, and β-site amyloid precursor protein cleaving enzyme (BACE1) were the target proteins. Molecular docking and 100 ns molecular dynamics (MD) simulations revealed that 3-O-galloylcatechin and 3-O-galloylepicatechin showed favorable interactions with AChE and GSK-3β, as they were able to outperform the positive controls in all of the studied parameters. However, the MM-GBSA binding free energy calculations revealed that only 3-O-galloylepicatechin, but not 3-O-galloylcatechin, outperformed the positive control of GSK-3β. Density functional theory (DFT) studies revealed that 3-O-galloylcatechin and 3-O-galloylepicatechin were stable and chemically reactive at the active sites of AChE and GSK-3β. The in-silico findings suggest that the observed in-vivo anti-Alzheimer activity of B. ciliata may be partly associated with the favorable molecular interactions of 3-O-galloylcatechin and 3-O-galloylepicatechin with AChE and GSK-3β. The current findings highlight the structural and mechanistic relevance of B. ciliata phytocompounds in modulating AD-associated targets. Based on the current findings, medicinal plants that contain 3-O-galloylcatechin and 3-O-galloylepicatechin may also be screened for their interactions with AD-related molecular targets. Show less

Alzheimer's disease (AD) and type 2 diabetes mellitus (DM), both of which are characterized by increased prevalence with aging, have considerable overlap in their risk factors, comorbidities and pathophysiological mechanisms including insulin resistance. While Alzheimer's β-secretase BACE1 is primarily expressed in the brain, it is also present in peripheral tissues at lower levels. Interestingly, BACE1 not only initiates the sequential cleavage of amyloid precursor protein to generate amyloid-β (Aβ) peptides but also cleaves the ectodomain of insulin receptors. Given a growing body of research showing that increased Aβ and insulin resistance elevate BACE1 level/activity, BACE1 represents a key molecule that is situated at the crossroads of a vicious circle between AD and DM. Remarkably, BACE1 level/activity is found to increase under insulin resistance in type 2 DM patients and animal models, which may represent a contributing factor to the progression to AD. This review provides an overview of BACE1 mechanism as a dual disease-modifying therapeutic target to mitigate Show less

A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer's disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer's research field. The present Perspective challenges this assumption. It analyses the relevant empirical data and reaches an unexpected conclusion, namely that in AD-afflicted neurons, the production of AβPP-derived Aβ is either discontinued or severely suppressed, a concept that, if proven, would fundamentally change our understanding of the disease. This suppression, effectively self-suppression, occurs in the context of the global inhibition of the cellular cap-dependent protein synthesis as a consequence of the neuronal integrated stress response (ISR) elicited by AβPP-derived intraneuronal Aβ ( Show less

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a central therapeutic target in Alzheimer's disease, as it catalyzes the rate-limiting step in amyloid-β production. Verubecestat (VER), a clinical BACE1 inhibitor, failed in late-stage trials due to limited efficacy and safety concerns. This study employed an integrative computational approach to design VER derivatives with improved binding affinity, stability, and pharmacokinetic profiles. Structural similarity analysis, Molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, 200 ns molecular dynamics (MD) simulations, MM/PBSA free energy calculations, and per-residue decomposition were performed. In silico ADMET profiling assessed drug-likeness, absorption, and safety parameters. Docking and pharmacophore analyses identified derivatives with stronger complementarity in the BACE1 catalytic pocket. MD simulations revealed that VERMOD-33 and VERMOD-57 maintained low root mean square deviations (RMSDs) and stable binding orientations and induced characteristic flexibility in the flap and catalytic loops surrounding the catalytic dyad (Asp93 and Asp289), consistent with inhibitory activity. MM/PBSA confirmed the superior binding free energies of VERMOD-33 (-51.12 kcal/mol) and VERMOD-57 (-43.85 kcal/mol), both outperforming native VER (-35.33 kcal/mol). Per-residue decomposition highlighted Asp93, Asp289, and adjacent flap residues as major energetic contributors. ADMET predictions indicated improved oral absorption, BBB penetration, and no mutagenicity or toxicity alerts. Rationally designed VER derivatives, particularly VERMOD-33 and VERMOD-57, displayed enhanced binding energetics, stable inhibitory dynamics, and favorable pharmacokinetic properties compared with native VER. These findings provide a computational framework for rescuing VER and support further synthesis and experimental validation of next-generation BACE1 inhibitors for Alzheimer's disease. Show less

Alzheimer's disease (AD) is a neurodegenerative condition characterized by a gradual decline in cognitive function, for which few effective treatments exist. This study investigated the neuroprotective potential of Show less

In quest of new and potent multitarget therapeutics for Alzheimer's disease (AD), a series of recently synthesized arylidene-hydrazinyl-thiazoles were repurposed as multitarget directed anti-AD agents. In total, 14 compounds were tested for their inhibitory activities against the key enzymes acetylcholinesterase (AChE), β-secretase 1 (BACE1), and butyrylcholinesterase (BChE). Derivatives Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated Show less

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-β (Aβ) generation and is considered promising drug target for Alzheimer's disease (AD). The co-chaperone BAG3 (Bcl-2-associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its degradation through ubiquitin-proteasome and autophagy-lysosomal pathways. BAG3 Show less

Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE-1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35 % inhibitory activity at 10 μM. Notably, pyrazole-5-carbohydrazide 29 (5784196) exhibited BACE-1 inhibition with an IC Show less