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Alzheimer's disease (AD) is the most common type of dementia with a complex pathobiology. The clinically approved treatments against AD attempt to provide only symptomatic relief. Therefore, the current findings highlighted the neuroprotective effect and the potential signaling mechanism of quinic acid (1) and its amide derivatives (2-4) against phytohaemagglutinin (PHA)-induced neurotoxicity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was conducted to assess the proliferative potential of 1-4 which were observed to increase the viability of SH-SY5Y cells. Microscopic examination of the cells induced with PHA and post treated with the respective test compound showed that 1 as well as its derivatives (2-4) improved morphology of the cells and subside the toxic effects of PHA. Evaluation of reactive oxygen species (ROS) production demonstrated that the test compounds except 4 decreased PHA-induced ROS in SH-SY5Y cells. The mRNA expression analysis of IL-1β, TNF-α, p38-α, p38-β and the disease associated ADAM10 and BACE1 genes revealed that 1 and its derivatives (2-4) reduced the PHA-induced elevated levels of inflammatory molecules whereas the compounds did not positively modulate the expression of proteolytic secretases. Moreover, the compounds reduced the disease specific increased expression of amyloid beta (Aβ), phosphorylated tau and activated p38 MAPK observed through fluorescence microscopy. Show less

Previous studies have reported that 40 Hz visual stimulation (acute white light exposure) reduced Aβ levels in Alzheimer's disease (AD) mouse model. However, whether different light colors distinctly regulate AD pathologies has not been well characterized. In the present study, an optimized organic light-emitting diode (OLED)-based visual stimulation platform was developed to provide uniform illumination without blind spots, and the color-dependent effects on cognitive function and amyloid-β (Aβ) pathology were investigated in 5xFAD mice, an Aβ-overexpressing AD model. Acute exposure to white or red OLED light (1 h/day for 2 days) significantly improved cognitive function, reduced hippocampal Aβ plaque accumulation via increasing ADAM17 activity, and downregulated proinflammatory cytokine IL-1β levels in 3-month-old 5xFAD mice, whereas green or blue OLED light did not produce these effects. In addition, chronic white and red OLED stimulation (1 h/day for 2 weeks) was shown to enhance recognition memory; however, only red light further diminished Aβ plaque deposition by upregulating ADAM17 activity and suppressing BACE-1 activity without altering neuroinflammation in 6-month-old 5xFAD mice. Moreover, acute white and red OLED exposure (1 h, single session) was observed to enhance c-fos expression, which is associated with neural activation along the visual pathway, thereby suggesting a mechanistic link between light stimulation and cognitive enhancement. Taken together, these findings demonstrate that color-dependent visual stimulation may serve as a promising electroceutical strategy for AD, with red light uniquely combining memory enhancement, Aβ reduction via ADAM17 upregulation and BACE1 suppression, and anti-inflammatory effects. Show less

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and the leading cause of cognitive decline in older adults. Several biomarkers of AD have been identified, but its pathogenesis has not yet been completely elucidated. One of the most relevant hypotheses proposed to explain the cognitive impairment caused by this disease is the cholinergic hypothesis, which postulates that loss of cholinergic neurons is one of its causes and that the subsequent reduction of acetylcholine levels in the synaptic cleft can be compensated through the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Another well-known hypothesis is the amyloid-beta hypothesis, which explains the disease as being caused by the formation and accumulation of amyloid plaques in a cascade of enzymatic events starting with the cleavage of an amyloid precursor protein (APP) by beta-secretase 1 (BACE-1). Previous studies have shown that silodosin has the structural requirements for the inhibition of those three enzymes (AChE, BuChE, and BACE-1), which suggests that it can be useful as a multitarget candidate to treat Alzheimer patients. This study aims to assess the effect of silodosin on cellular viability, measure the inhibitory activity against AChE, BuChE, and BACE-1, and evaluate the molecular behavior of all three inhibitor-enzyme systems by molecular dynamics (MD) simulations. Cell viability assays through the MTT method showed that silodosin concentrations of less than 10 μM are safe to be used. Enzymatic assays revealed AChE inhibitory activity at high micromolar levels (IC50 >500.0 μM) but inhibited BuChE at low micromolar levels (IC50 = 3.02 ± 0.05 μM). BACE-1 inhibition assays have shown significant reduction at three micromolar. MD simulations demonstrated that silodosin promotes late stabilization of the AChE complex, but the simulations involving BuChE and BACE-1 revealed that the compound promotes system stabilization at early stages and has the structural requirements to inhibition. Show less

Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and neurodegeneration. Since the amyloid cascade hypothesis was proposed, Aβ has remained a central therapeutic target, with interventions aiming to reduce Aβ production, aggregation, or downstream toxicity. This review first outlines the historical development of the Aβ hypothesis and the two major APP processing pathways (α-cleavage and β-cleavage), highlighting the role of biomarkers in early diagnosis, patient stratification, and regulatory approval. We then summarize the development and clinical outcomes of anti-Aβ small-molecule drugs, including β-secretase inhibitors, γ-secretase modulators, Aβ aggregation inhibitors, receptor/synapse modulators, and metabolic or antioxidant modalities. We further review the progression of biologic therapies, with a particular focus on monoclonal antibodies, vaccines, and emerging gene-silencing strategies, such as small interfering RNA (siRNA) and antisense oligonucleotides. Finally, we discuss future perspectives, including next-generation biologics, multi-target approaches, optimized delivery platforms, and early-prevention strategies. Collectively, these efforts underscore both the challenges and opportunities in translating anti-Aβ therapies into meaningful clinical benefits for patients with AD. Show less

Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, poses a significant global health challenge with complicated pathogenesis. Pathological characteristics of AD include increasing loss of cholinergic neurons, oxidative stress, mitochondrial dysfunction, and amyloid beta accumulation. Due to the limited availability of effective therapeutic options with only symptomatic relief and their severe adverse effects, there is a significant need to search and explore new agents for the management of AD. Recently, natural products and/or phytoconstituents of plants have gained notable attention as potential sources of neuroprotective agents due to their diverse chemical constituents, mechanism of action, and relatively safe profiles. In view of this, Glycyrrhiza glabra has been recognized for its several therapeutic properties in traditional medicine systems for centuries. Further, neuroactive phytoconstituents of this plant, including glycyrrhizin, liquiritigenin, isoliquiritigenin, glabridin, and glycyrrhizic acid, exhibit significant pharmacological advantages along with potential neuroprotective effects against AD. Show less

Alzheimer's and Parkinson's disease are the most prevalent neurological diseases. Amyloid-β, tau, and α-synuclein proteins are known to be implicated in neurodegenerative disease (NDD). Elucidation of precise therapeutic targets remains a challenge. Therefore, the identification of interactomes of amyloid-β precursor protein (APP), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) proteins is of great interest, aimed at unraveling novel targets. An integrated analysis was employed to identify direct interactors as therapeutic targets, considering protein-protein interactions and subsequent network analysis. Further, it was proposed to identify hub proteins, intended targets, regulatory factors, disease-gene associations, functional enrichment analyses of the protein interactors interfered with gene ontologies and disease-driving pathways. Protein interactome centered on APP, MAPT, and SNCA identified the top hundred high-confidence protein-protein interactions that revealed BACE1, PSEN1, SORL1, GSK3B, CDK5, SNCAIP, PRKN, and APOE as physical and functional protein interactors. The top ten hub proteins were ranked based on multiple centrality measures and topological algorithms. Further, the integrated network of all three protein interactomes contained distinct nodes with edges. Interestingly, regulatory mechanisms have revealed possible regulatory modules, including cleavage, phosphorylation, and ubiquitination. Top interacting proteins were enriched in several ontology terms, such as regulation of neuronal apoptotic processes, amyloid beta fibril formation, and tau protein binding. Pathway analysis mapped the pathways of neurodegeneration-multiple disease, with a significant level of interacting proteins. Finally, the most comprehensive interactome associated with NDD provides insights into protein interactors, regulating the mechanisms of key proteins that can serve as novel therapeutic targets. Show less

To investigate the role of lncRNA BACE1-AS in neuronal injury and neurological deficits after ischemic stroke and explore its underlying molecular mechanism. MCAO rat model and OGD/R cell model were established. BACE1-AS expression was detected by RT-qPCR. Neurological function was evaluated by mNSS and MWM test. Inflammatory factors (TNF-α, IL-6, IL-10), neuronal injury markers (NSE, GFAP), and apoptosis-related markers (Bcl-2, Bax, Caspase-3) were detected by ELISA and RT-qPCR. Bioinformatics analysis, dual-luciferase reporter assay, and RIP assay were used to validate the targeting relationship between BACE1-AS and miR-103a-3p. BACE1-AS was significantly upregulated in both MCAO rats and OGD/R-treated SH-SY5Y cells. Silencing BACE1-AS alleviated neurological deficits, reduced pro-inflammatory cytokine levels, and inhibited neuronal apoptosis. Mechanistically, BACE1-AS targeted miR-103a-3p, and inhibiting miR-103a-3p reversed the neuroprotective effects of BACE1-AS silencing in vivo and in vitro. Silencing BACE1-AS mitigates neuronal injury and neurological deficits after ischemic stroke by targeting miR-103a-3p, providing a novel therapeutic target for ischemic stroke. Show less

Sleep disorders show comorbidity with depression and Alzheimer's disease (AD), especially in ageing. However, the neuroimmunological role of sleep deprivation (SD) as possible inducer to these conditions remains unknown. Omega-3 fatty acids (n-3 FAs) can improve depression and AD through anti-inflammation, up-regulating neurotrophins and normalizing neurotransmitters, while their therapeutic effects on sleep deprivation (SD)-induced changes in different ages requires investigation. Adult and old Fat-1 (converting n-6 to n-3 FAs) and wild-type (WT) mice were subjected to chronic SD. After behavioral evaluation, brain FAs, monoamine neurotransmitters, circadian-gene expression, TLR-4 signaling-pathway, glial polarization, cytokine profile, and AD-related markers were analyzed using GC-MS, HPLC, qPCR, ELISA and western-blotting. Furthermore, bioinformatic analysis evaluated SD-related networking with depression and AD. SD induced anxiety, anhedonia, despair, and memory impairments. The n-3:n-6 ratio, BMAL-1 gene expression, and melatonin concentration were decreased, whereas corticosterone, TLR-4, GSK3β, and NFκB concentrations increased in SD groups compared to the controls. Increased IBA-1 protein expression and proinflammatory IL-1β, TNF-α, and IL-6 concentrations were associated with decreased monoamine neuro-transmitter levels in SD groups. APP, BACE-1, RAGE and APPβ concentrations were increased, whereas LRP-1 and APPα concentrations and the APPα/APPβ ratio were decreased in SD groups than controls. These changes were more pronounced in old WT and Fat-1 animals than adults. However, compared to WT-SD, these changes were significantly ameliorated in Fat-1-SD mice, but recovery was less pronounced in old Fat-1. SD-induced neuroinflammation and impaired APP processing may contribute to behavioral impairments, which exacerbated with age. Although n-3 FAs significantly ameliorated SD-induced adverse behavioral and neuroimmunological changes, this therapeutic effect was markedly reduced in old animals. Show less

Aberrant aggregation of amyloid-β (Aβ) peptides is a hallmark of Alzheimer's disease (AD), contributing to synaptic dysfunction and cognitive decline. Recently, pyroglutamate-modified Aβ (pE3-Aβ) has emerged as a key contributor to Aβ pathology, as it is a highly aggregation-prone variant that enhances amyloid seeding and accelerates plaque propagation. β-Secretase (BACE1) and glutaminyl cyclase (QC) are essential enzymes for generating Aβ and pE3-Aβ, respectively, and represent key therapeutic targets. This study evaluated fucoxanthin, a marine carotenoid found in brown algae for its potential to modulate Aβ pathology and cognitive function. In SweAPP N2a cells, fucoxanthin (0.1-5 μM) significantly decreased BACE1 and QC expression, accompanied by reduced levels of Aβ Show less

Low vitamin D levels are associated with an elevated risk of Alzheimer's disease (AD). Given the rising prevalence of diabetes and its association with AD, this study investigated whether vitamin D modulates amyloidogenesis and inflammation in the brains of diabetic mice. Five-week-old male C57BLKS/J- High dietary vitamin D levels attenuated neuronal necrosis in db/db mice. Hippocampal These findings suggest that vitamin D may exert neuroprotective effects on the hippocampus and PFC in diabetic mice by mitigating neuronal damage and suppressing amyloidogenic and inflammatory gene expression. Show less

Dysferlin direct protein-protein interactions (PPI) previously have been elucidated with surface plasmon resonance (SPR) and predicted to underlie membrane repair in mechanotransducing myofibrils. In mechanotransducing inner ear hair cells, dysferlin is detected with Z-stack confocal immunofluorescence in the stereocilia and their inserts in the tectorial membrane (TM) co-localizing with FKBP8, consistent with the SPR determination of tight, positively Ca Show less

Previous research has reported the efficacy of porcine brain hydrolysate (PBH) in improving Alzheimer's disease (AD). Nevertheless, the identification and screening of peptides with memory-enhancing effects within PBH remains ambiguous. The memory-enhancing effect of PBH was evaluated through animal and human experiments. Peptides with potential memory-enhancement effects were screened using molecular docking based on key target proteins (Keap1, BACE1, AChE, and p38α), and confirmed through cellular experiments. Results showed a significant reduction in behavioral errors of mice and marked improvements in the memory scores of humans. Five peptides with potential memory-enhancing effects were identified and screened. Cell experiments demonstrated that the cell activities were increased to 89.83 % and 78.14 % respectively for FPLHP and WGQKPW. Furthermore, the two peptides could reduce the contents of the four target proteins, thereby exhibiting the potential of memory enhancement. These findings offer a novel strategy for the discovery of peptides, which contribute to the development of memory-enhancing. Show less

Alzheimer's disease (AD) is a neurodegenerative disease characterized by abnormal accumulation of β-amyloid (Aβ) and hyperphosphorylation of the Tau protein. Currently, there is a lack of effective and safe therapeutic approaches. In Traditional Chinese medicine (TCM), Gandou Decoction has shown significant efficacy in improving cognitive decline and dementia-related symptoms, but its specific mechanism remains unclear. This study systematically analyzed the active components and anti-AD mechanism of Modified Gandou Decoction (MGD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics (MD) simulation, and A total of 21 potential active molecules of MGD and 68 intersection targets were screened out. Among them, 8 core targets (EIF2AK2, PPARG, BACE1, ESR1, GSK3B, ACE, CASP3, MAPK14) were confirmed to be significantly associated with AD pathology by gene expression difference analysis (P ≤ 0.05). KEGG enrichment analysis showed that MGD mainly intervenes in the amyloid production pathway, the MAPK pathway, and the IL-17 pathway. Molecular docking demonstrated that the majority of the 21 potential active compounds exhibited strong binding affinities to the 8 core targets. Moreover, some potential active molecules exhibited better binding energy and similar binding modes compared with known inhibitors when binding to the corresponding target proteins. Molecular dynamics simulation showed that Alisol B, a potential active component of MGD, could stably bind to BACE1, EIF2AK2, and CASP3. MGD exerts its anti-AD effect through its potential active component Alisol B, which binds to target proteins BACE1, EIF2AK2, and CASP3, and synergistically inhibits Aβ production, Tau phosphorylation, and neuroinflammatory processes through multiple pathways. This study provides a foundation for developing MGD-derived natural products for AD treatment, although the precise mechanisms require further experimental validation. Show less

Bushen Huoxue Acupuncture shows potential in treating neurodegenerative diseases, but its mechanisms remain incompletely understood. Using the senescence-accelerated mouse-prone 8 (SAMP8) mouse model, we assessed cognitive function via the Morris water maze test, hippocampal neuronal apoptosis with terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and microglial activation through immunohistochemistry. Serum levels of inflammatory cytokines [tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6] were quantified by enzyme-linked immunosorbent assay. The expression of SIRT2 pathway-related proteins, along with Aβ deposition, was analyzed using Western blotting, immunohistochemistry, and immunofluorescence. The results demonstrated that Bushen Huoxue Acupuncture improved cognitive function in SAMP8 mice, reducing hippocampal neuronal apoptosis and decreasing serum levels of pro-inflammatory cytokines. Additionally, it reduced the levels of Aβ42, a more aggregation-prone and toxic Aβ subtype, in both hippocampal tissues and serum, as well as the number of CD68-positive cells in hippocampal tissues, suggesting the inhibition of amyloid pathology and neuroinflammatory. The treatment also downregulated SIRT2, BACE1, and APP-CTF while increasing RTN4B expression. Notably, Bushen Huoxue Acupuncture outperformed non-acupoint acupuncture in enhancing cognitive function and reducing inflammation. Our findings indicate that Bushen Huoxue Acupuncture alleviates cognitive deficits and neuroinflammation by suppressing the SIRT2-mediated RTN4B/BACE1 pathway, highlighting acupuncture as a promising therapy for neurodegenerative diseases. Show less

Present paper elicits the synthesis of a series of 2,2-dimethyl-2H-[1,3]dioxino[4,5-b]pyrrol-4(7H)-one derivatives as novel selective BACE1 inhibitors for the treatment of Alzheimer's disease (AD). A four-component, solvent-free condensation process, catalyzed by 10 mol% NiCl₂·6H₂O strategy was explored to achieve their synthesis. The structures of the synthesized compounds were ascertained using different spectroscopic techniques, including FT-IR, Show less

Alzheimer's disease is a neurodegenerative disorder that causes significant cognitive impairment and memory loss. It is the leading cause of dementia on a global scale and is distinguished by the pathological build-up of amyloid-beta peptides and tau protein. This study presents the development of E-pharmacophore modeling, which utilizes reported co-crystal structure involving beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) to screen the eMolecules database. The present study comprehensively dealt with the virtual screening and structure-based prediction of thiazole compounds against BACE1 protein. To investigate the binding mode of virtual-screened hits (VS-hits), top 100 VS-hits were docked into BACE1 followed by in silico ADMET prediction. Top two VS-hits (CP1 and CP2) with highest docking scores along with co-crystalized ligand (CPZ) were further subjected to MESP, HOMO, LUMO, MD simulation, and MMGBSA analysis to inspect the dynamic stability of inhibitor-BACE1 complexes and the key molecular interaction responsible for their improved binding affinity toward BACE1. This research identified CP1 and CP2 as top two potential novel BACE1 inhibitors from the library of natural products, whose Glide docking scores range from -8.87 to -7.89 kcal/mol-1. Interestingly, both ligands were able to establish interactions with a set of conserved residues F108, I110, I118, L30, Q12, G13, G11, A335, S229, D228, G230, D32, G34, S35, and Y71. ADMET assessment of the selected compounds was also noted to be within acceptable ranges. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The RMSD and RMSF analysis revealed that both ligands remained stable and maintained their interaction throughout the simulation time (100 nanoseconds). The MM/GBSA (ranging from -36.734 to -27.431 kcal/mol) predicted binding affinities are in strong correlation with that of the docking score, which not only supports the docking results but also suggests that CP1 exhibits superior binding affinity towards BACE1. Keeping in view these findings, CP1 might be a promising candidate for drug discovery against BACE1 inhibitors. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious BACE1 inhibitors. Show less

The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target. We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms-including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease-to dissect its tissue-specific pathophysiological impacts. The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling. The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies-including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)-offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, neuroinflammation, and neuronal apoptosis. Trofinetide, an analog of insulin-like growth factor 1 (IGF-1), has shown neuroprotective effects in various neurological disorders, but its role in AD remains unclear. Six-month-old APP/PS1 transgenic mice received intraperitoneal trofinetide for 2 months. Cognitive function was assessed using the Morris water maze (MWM) test. Immunohistochemistry (IHC) and immunofluorescence (IF) evaluated β-amyloid (Aβ) pathology, microglial activation, and neuronal loss. In vitro, BV2 microglial cells and HT22 hippocampal neurons were treated with trofinetide against AβO-induced cytotoxicity. Western blot (WB) was used to analyze inflammation and apoptosis-related proteins. Trofinetide significantly improved cognitive deficits, reduced Aβ plaque deposition, and decreased microglial activation and neuronal loss in APP/PS1 mice. In vitro, it rescued AβO-induced cytotoxicity, suppressed inflammatory cytokines (TNF-α, IL-6, IL-1) in BV2 cells, and inhibited apoptosis in HT22 cells. Mechanistically, trofinetide upregulated PPAR-γ, reduced BACE1, suppressed NF-κB phosphorylation, inhibited caspase-3 activation, and restored Bax/Bcl-2 balance, alleviating neuroinflammation and apoptosis. This study provides the first evidence that trofinetide improves cognitive function and mitigates Aβ pathology, neuroinflammation, and apoptosis in APP/PS1 mice and AβO-treated cells, highlighting its therapeutic potential for AD. Show less

BACE1 is an indispensable enzyme for the production of β-amyloid peptides by initiating the cleavage of amyloid precursor protein at the β-secretase site. Targeting BACE1 inhibition is therefore a therapeutic strategy for treating patients with Alzheimer's disease. However, several clinical trials using brain-penetrable BACE1 inhibitors have failed due to a lack of efficacy. Previous studies, including our own, have shown that both global and neuron-specific BACE1 inhibition in mice leads to impairments in synaptic strength and spine density. In this study, we investigate the effects of BACE1 inhibition on activity-dependent synaptic vesicle exocytosis and endocytosis using a synapto-pHluorin mouse model. Our results demonstrate impaired synaptic release in BACE1-deficient mice. Furthermore, transcriptomic analysis reveals a significant downregulation of genes related to synapse structure and function. Pathway analysis suggests that BACE1 deficiency significantly downregulates neurexin-neuroligin pathway, which can modulate docking and release of synaptic vesicles at the presynaptic compartment. Our findings suggest that BACE1 inhibition may lead to deficits in synaptic vesicle exocytosis due to the downregulation of key synaptic proteins. Show less

Viral and neurodegenerative proteases, such as the cysteine protease and aspartyl protease, offer strategic targets in a multitarget therapeutic approach for Alzheimer's disease, especially when viral infection may exacerbate neurological degeneration. To establish a multitarget therapeutic for treating Alzheimer's disease, we chose β-secretase (BACE-1), an aspartyl protease, and the SARS-CoV-2 main protease (Mpro), a cysteine protease, as dual targets. In search of BACE-1 and M Show less

This objective of this study was to investigate how aluminum affects the PKA-PGC1α-BACE1 pathway in PC12 cells and its role in neurotoxicity. According to the exposure dose of aluminum maltol, PC12 cells were selected for research and divided into five experimental groups and six intervention groups. After 24 h of 8-Bromo-cAMP intervention, they were treated with Al-(mal) Under the microscope, the number of cells in the aluminum maltol group decreased, the morphology changed, and the number of intercellular connections decreased. However, after treatment with the 8-Bromo-cAMP agonist, a significant increase in the number of cells was observed, and significant morphological changes occurred, with a gradual increase in intercellular connections. CCK-8 assays showed that cell viability gradually decreased with increasing aluminum exposure doses. Western blot showed that PKA and PGC1α expressions decreased with higher aluminum doses, while BACE1 increased; agonist treatment upregulated PGC1α and downregulated BACE1, with minimal effect on PKA; and ELISA results indicated that aluminum reduced PKA enzyme activity but increased BACE1 activity and Aβ levels. Exposure to aluminum inhibits the PKA-PGC1α-BACE1 signaling pathway, while PKA agonists can alleviate neurotoxicity by restoring this pathway. Show less

Effect on amyloid plaque as measured by positron emission tomography imaging with Centiloid standardization of two therapeutic approaches targeting amyloid beta (Aβ) was investigated using exposure-response modeling. Individual-level verubecestat data from the APECS trial were pooled with summary-level data from the literature for amyloid monoclonal antibodies (mAbs) and fitted in a joint non-linear mixed-effects model. An indirect-response (turnover) model with verubecestat inhibiting plaque formation and mAbs stimulating plaque removal well represented the data. The estimated plaque elimination half-life was 6.4 years. Daily verubecestat 40 mg was estimated to reduce formation by 91.8%. Aducanumab 10 mg/kg every 4 weeks (Q4W), donanemab 1400 mg Q4W, gantenerumab 1200 mg Q4W, and lecanemab 10 mg/kg Q2W were estimated to increase the removal rate by 9.3-, 18.6-, 5.3-, and 13.8-fold, respectively. The model provides a fundamental measure of drug effects on plaque, independent of disease stage and study-design factors, improving cross-study comparisons and enabling predictions. The plaque turnover model describes natural progression and BACE and mAb intervention.The model estimation of the underlying plaque elimination half-life is 6.4 years.Approach improves cross-study comparison independently of population and study design.Predictions of alternative regimens/therapeutic approaches will aid future study design. Show less

Neurodegenerative diseases, particularly Alzheimer's disease (AD), represent a significant public health challenge due to their increasing prevalence and the lack of effective treatments. In this study, we explored the neuroprotective effects of beta-carotene, a naturally occurring carotenoid, by investigating its ability to inhibit or reduce apoptosis and inflammation while enhancing antioxidant potential in SH-SY5Y neuroblastoma cells. Beta-carotene was extracted from Chlorella vulgaris using high-performance liquid chromatography (HPLC). We utilized SH-SY5Y cells, a widely employed in vitro model for studying neurodegenerative processes, to evaluate these therapeutic effects. A combination of colorimetric assays, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time PCR (qRT-PCR) was used to assess the impact of beta-carotene on enzyme activity, cytokine production, and gene expression. The caspase assay results demonstrated that beta-carotene effectively reduced the activity of pro-apoptotic caspases and downregulated the expression of pro-apoptotic genes such as Bax, Bak and caspases, thereby inhibiting apoptosis in SH-SY5Y cells. Additionally, beta-carotene exhibited potent antioxidant properties by upregulating NRF2 and superoxide dismutase (SOD), along with enhancing ABTS and DPPH radical scavenging activities.showed antiinflamatory effects reduce the concentrations of proinflamatory cytokines TNFα, IL-1 β and IFN-γ, and supress the inflamtion patway by supressing the expression of Akt, PIK3, STAT1 and NF-kB, Akt etc. Importantly, beta-carotene treatment led to the suppression of β-secretase (BACE1), γ-secretase and acetylcholinesterase (AChE) activities, and the downregulation of genes involved in amyloid-beta production, including BACE1, and PECN1 eventualy resulted in dcerase concentration o Aβ peptides. These findings suggest that β-carotene could be a promising therapeutic candidate for the prevention and treatment of neurodegenerative diseases, particularly Alzheimer's disease, however further investigations are recomended in animal models and clinical trials before incorporating beta-cerotene into pharmaceutical formulations for AD treatment. Show less

Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD. Show less

Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is associated with the pathoprogression of neurodevelopmental and neurodegenerative disorders. However, the effects of direct genetic manipulation of DYRK1A in the brain on cognitive function, neuroinflammation and Alzheimer's disease (AD) pathology and underlying molecular mechanisms have not been fully investigated. To determine whether overexpressing or knocking down DYRK1A expression directly in the brain affects cognitive function, neuroinflammation and AD pathology, adeno-associated viruses (AAVs) were injected into the hippocampus of wild-type (WT), 5xFAD, and PS19 mice. Then, cognitive function was assessed via Y-maze and novel object recognition (NOR) tests, and neuroinflammatory responses and AD pathologies were analyzed by real-time PCR, Western blotting, immunofluorescence staining, AD-associated protein activity assays and ELISA. In WT mice, hippocampal DYRK1A overexpression significantly reduced short-term spatial/recognition memory and SynGAP expression while increasing p-P38 levels. Conversely, in amyloid-beta (Aβ)-overexpressing 5xFAD mice, hippocampal DYRK1A knockdown improved short-term spatial/recognition memory and significantly increased CaMKIIα and CREB phosphorylation. Moreover, hippocampal DYRK1A knockdown in 5xFAD mice significantly suppressed mRNA levels of proinflammatory cytokines and markers of AD-associated reactive astrocytes (RAs), disease-associated microglia (DAMs), and RA-DAM interactions. However, hippocampal DYRK1A overexpression in 5xFAD mice increased mRNA levels of the proinflammatory cytokine IL-1β, RA markers and the microglial marker Iba-1. Interestingly, hippocampal DYRK1A knockdown in 5xFAD mice significantly increased levels of the anti-oxidative/inflammatory molecule HO-1 without altering p-STAT3/p-NF-κB levels. By contrast, hippocampal DYRK1A overexpression in 5xFAD mice enhanced STAT3/NF-κB phosphorylation but did not affect ROS levels. Importantly, hippocampal DYRK1A knockdown in 5xFAD mice significantly reduced Aβ plaque number, soluble Aβ40 levels, and soluble/insoluble Aβ42 levels by suppressing β-secretase BACE1 activity but not tau hyperphosphorylation. Finally, hippocampal DYRK1A knockdown in PS19 mice [a model of AD that overexpresses human mutant tau (P301S)] selectively decreased insoluble tau hyperphosphorylation at Ser396 and Ser404 and alleviated proinflammatory responses/glial-associated neuroinflammatory dynamics. Taken together, our data indicate that DYRK1A modulates cognitive function, neuroinflammation, and AD pathology (Aβ and tauopathy) in mouse models of AD and/or WT mice and support DYRK1A as a potential therapeutic target for AD. Show less

Alzheimer's disease (AD) is a leading cause of dementia worldwide and continues to be one of the most frequently diagnosed neurodegenerative disorders in adults aged 65 and older. While much progress has been made in exploring AD pathophysiology, there remains no current cure, and symptomatic treatment is the current standard at best. As life expectancy continues to rise, the global prevalence of AD is increasing, making it evident that new therapeutic strategies are sorely needed. The etiology of AD is complex and heterogeneous, with cholinergic dysfunction, taurelated dysfunction, amyloid cascade dysfunction, oxidative dysfunction, and neuroinflammation all contributing to the unique pathology. As a result, researchers are focused on safe and effective drug candidates capable of addressing all of these interrelated mechanisms. One group of such multidrug candidates is benzimidazole derivatives, which target numerous molecular targets, such as, but not limited to, cyclin-dependent kinase 5 (CDK5), tau protein, acetylcholinesterase (AChE), betasecretase 1 (BACE1), serotonin receptor 5-HT4, cannabinoid receptor CB2R, and the gammaaminobutyric acid receptor A (GABA-A). This study reveals the multitargeting promise of benzimidazole- based compounds that regulate not just symptomatic pathways but also pathways that are responsible for modifying AD disease activity. Ongoing studies in this area may lead to the discovery of new drugs that can not only manage the symptoms but also change the trajectory of this serious disease and provide hope to millions of AD patients. Show less