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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

The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis and mechanisms of this medicine are still unclear. Isoliensinine (IL) is a major alkaloid derived from lotus embryos. Our previous research has demonstrated that IL can exert strong anti-inflammatory and neuroprotective effects in vitro. To reveal the underlying therapeutic effect and mechanism of IL on Alzheimer's disease (AD)-like mice induced by AlCl The AD-like mice were modeled by intragastric injection (i.g.) of AlCl IL (1, 3, and 10 mg/kg) treatment effectively ameliorated cognitive impairment in AD-like model mice. IL inhibited the decrease of brain index and body weight in AD-like mice and alleviated neuronal damage in the cortex and hippocampus (DG, CA1, and CA3). IL decreased the levels of Ca IL has a significant therapeutic effect on pathological alterations and cognitive impairment in AlCl Show less

Alzheimer's Disease (AD) is a brain disorder with various neuropathological hallmarks and has become a major concern globally due to limited therapeutic options. Cholinergic dysfunction due to the depletion of acetylcholine (ACh) levels in the synapse caused by increased acetylcholinesterase (AChE) activity is one of the major factors that drives AD progression. AChE also accelerates amyloid beta (Aβ) formation and leads to amyloid plaque deposition in the brain. Production of Aβ from amyloid precursor protein (APP) with sequential cleavage by β-secretase (BACE1) and γ-secretase causes severe brain damage due to plaque toxicity. Neurofibrillary tangles (NFTs), a neuronal catastrophe resulting from hyperphosphorylation of tau protein due to upregulation of glycogen synthase kinase 3 beta (GSK3β) and downregulation of Wnt signaling because of Dickkopf-1 and low density lipoprotein receptor-related protein 6 (DKK1-LRP6) interaction, are a major pathogenic event in AD. Recent research has increasingly focused on targeting amyloidopathy, tauopathy, and cholinergic pathways as therapeutic strategies for mitigating AD pathology. Coptisine, a bioactive alkaloid having enormous pharmacological properties, including neuroprotective action, is considered in our in-silico investigation. Collective inhibition of key targets in AD pathogenesis, like AChE, β-secretase (BACE1), γ-secretase, GSK3β, and DKK1-LRP6 interaction, could be a positive approach in the arsenal of Alzheimer's treatment. In this article, we report that coptisine can inhibit these five major targets as evident from our molecular docking study, and propose it as a potential multi-target drug to play a key role in halting AD pathology. Further, comparative analysis based on predicted values of cheminformatics and pharmacokinetic profiling of coptisine and known inhibitors increases its possibility to ameliorate AD. However, robust research, including a preclinical and clinical study on coptisine for its safety and efficacy assessment against AD pathology, is warranted for its validation as an anti-AD drug. Show less

Heat shock proteins (HSPs) are molecular chaperones that play important roles in protein homeostasis, with HSP70 linked to a role in neuroprotection. HSP70 is upregulated in response to various stressors, such as heat therapy (HT), which has been shown to increase brain-derived neurotrophic factor (BDNF) content. BDNF reduces the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the rate-limiting enzyme responsible for the generation of amyloid-β (Aβ) peptides that form the characteristic Aβ plaques observed in Alzheimer's disease brains. The current pilot study examined whether 4 wk of HT can increase HSP70 and BDNF content (pro and mature forms) in the brain, and alter markers of amyloid precursor protein (APP) processing. Male mice had their core temperature maintained between 37.0 and 38.0°C in Control (CON, 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

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β Show less

Patients with Alzheimer's disease (AD) demonstrate brain mitochondrial dysfunction and energy deficiency that are closely associated with cognitive impairment. Cytochrome c oxidase (CCO), also known as mitochondrial complex IV, is the terminal enzyme in mitochondrial electron transport chain (ETC). Consistent with the pivotal role of CCO in mitochondrial bioenergetics and high demand for energy to sustain neuronal function, CCO dysfunction has been linked to neurological disorders including AD. However, it remains unclear whether mitochondrial CCO dysfunction represents an adaptive response to AD-associated toxic molecules versus a 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

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Current single-target interventions fail to halt disease progression, highlighting the need for multi-target strategies. This study investigates the therapeutic potential and mechanisms of ZuoGui Pill (ZGP), a traditional Chinese medicine formula, in a transgenic AD mouse model. 3xTg-AD mice were treated with ZGP for 60 days. Behavioral performance was assessed using the Morris water maze, novel object recognition, and open field test. Aβ deposition, tau phosphorylation, and synaptic integrity were evaluated via immunohistochemistry, Western blotting, RT-qPCR, and Golgi staining. Neuroinflammation and RAGE/NF-κB signaling were analyzed by ELISA and protein expression profiling. Statistical analyses included ANOVA with post hoc Tukey or Bonferroni tests following Shapiro-Wilk and Bartlett's validation. ZGP significantly improved cognitive performance, reduced hippocampal Aβ deposition and BACE1 expression, and suppressed tau phosphorylation at multiple pathological sites (T205, S396, S404). Synaptic markers (Syn, PSD95) were restored, accompanied by increased dendritic spine density. ZGP also reduced hippocampal IL-1β, IL-6, and TNF-α levels and inhibited the RAGE/p-NF-κB pathway. ZGP exerts multi-target neuroprotective effects in 3xTg-AD mice by modulating Aβ and tau pathologies, preserving synaptic structure, and attenuating RAGE-mediated neuroinflammation. These findings support ZGP as a promising integrative therapeutic strategy for AD. 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

Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60-70 % of cases. β-secretase 1 (BACE1), is one of the main therapeutic targets involved in the disease's pathology, as it is involved in the production of amyloid β. Butrylcholinesterase (BuChE) which is active in the advanced stages of the disease, is targeted for symptomatic relief. AD is a complex illness that needs to be tackled from different angles for which the Multi-target inhibitor approach is a viable current strategy. This work focuses on the development of novel acyl-oxindole molecules - some containing fluorine units, obtained via a structure-based drug design approach, for inhibition of BACE1 and BuChE. This study explored the development of a sustainable metal-based synthetic procedure for rapid and sustainable assess of libraries of these new oxindole derivatives. The compounds were screened to determine their ability to inhibit BACE1, and demonstrated reasonable levels of inhibition, with some of these inhibitors being selected for docking studies to determine the binding mode to the target's active site. One of the key molecules 12a underwent a cytotoxicity screen in a mouse neuroblastoma cell line expressing the APPswe protein (N2A-APPswe cells) and was an inhibitor of both AChE and BuChE (more potent against the latter, including the human version). Some compounds (3a, 3b, 3i and 12a) have shown moderate BuChE inhibitory activity. 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

Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration. 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

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

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. 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

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

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

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