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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

Mangiferin, a chemical constituent of Mangifera indica, has been the subject of extensive investigation due to its diverse biological activities, as detailed in numerous scientific studies. Its aglycone, norathyriol, has similarly garnered attention from researchers. In furtherance of our ongoing research goals, this article presents an evaluation of these compounds in relation to biomarkers associated with Alzheimer's disease. The inhibition of acetylcholinesterase (AChE) and β-secretase (BACE-1), as well as the aggregation of the amyloid beta (Aβ)42 peptide, was assessed using Ellman's colourimetric method, fluorescence resonance energy transfer (FRET), and thioflavin-T fluorescence emission, respectively. Mangiferin exhibited no inhibitory effect on AChE, whereas norathyriol demonstrated an inhibitory concentration (IC50) of 6.23 μM. Molecular docking revealed that the mangiferin-AChE and mangiferin-BACE-1 complexes did not interact with sites related to enzyme activity. In contrast, norathyriol showed favourable interactions with Asp72 at the peripheral site of AChE and formed significant interactions with BACE-1 through hydrogen bonds, as suggested by molecular docking. The IC50 of norathyriol for BACE-1 inhibition was found to be 9.75 μM. The reduction in Aβ42 aggregation by norathyriol was only 28%. We conclude that norathyriol is a promising prototype for drug development aimed at treating Alzheimer's disease. 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

To explore the mechanism by which BALB/c mice were infected by intraperitoneal injection with TgCtwh3 wild type (TgCtwh3 WT) and TgCtwh3 Δ BALB/c mice injected with TgCtwh3 Δ Our results indicated that the GRA15 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) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn 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

Alzheimer’s disease (AD) is a leading cause of dementia, imposing a substantial burden on individuals and society. While existing therapies can reduce the symptoms of AD, they do not offer genuine therapeutic effectiveness. Adiponectin Receptor Agonist (ADN-R Ag) has been proposed as a novel therapeutic agent for AD. This study aims to evaluate its efficacy in treating AD model mice. A systematic search of PubMed, Scopus, Cochrane Library, and Web of Science was conducted up to May 3, 2025. Research investigating the impact of ADN-R Ag on cognitive performance and associated molecular pathways in Alzheimer’s disease models, specifically APP/PS1, P301S, and 5XFAD mice, was incorporated. The Alzheimer’s disease models in the study were male and ranged in age from 5.5 to 8 months. Studies evaluating the effect of ADN-R Ag on AD model mice through cognitive function tests and related molecular mechanisms were included. Methodological quality assessment was performed using the CAMARADES tool for animal studies. The meta-analysis was performed following Cochrane guidelines. Six articles were included for the review. ADN-R Ag significantly improved cognitive function in the meta-analysis. The weighted mean difference of ADN-R Ag was 21.75 (95% CI: 16.61–26.88; Based on the current study, ADN-R Ag has therapeutic effects on AD. However, considering the complex underlying molecular mechanisms and limited prior studies, further research is needed. The online version contains supplementary material available at 10.1186/s12883-025-04356-5. 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

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), and neuroinflammation, leading to progressive cognitive decline. Research has increasingly emphasized the importance of a nutritious diet rich in phytochemicals that promotes brain health and potentially mitigates the risk or progression of neurodegenerative diseases, such as AD. Resveratrol (RSV), a natural polyphenol with known anti-inflammatory, antioxidant, antiapoptotic, and neuroprotective properties, has thus garnered significant attention. This review examines the potential of RSV in modulating AD pathophysiology, drawing from preclinical and clinical investigations. Preclinical studies demonstrate RSV reduces Aβ accumulation by modulating BACE1, enhancing neprilysin activity, inhibiting aggregation, and promoting clearance. RSV also attenuates Tau phosphorylation in animal models, suggesting its potential to target both hallmark AD pathologies. Furthermore, RSV exhibits anti-inflammatory properties by reducing microglial activation and proinflammatory markers. Clinical trials indicate that RSV may attenuate declines in CSF Aβ40 levels and reduce CSF MMP9 levels, indicating potential benefits in Aβ pathology and neuroinflammation in select studies. However, its impact on tau remains inconclusive. Some clinical studies have shown trends toward cognitive benefits, particularly in functional measures such as ADCS-ADL; however, these findings are inconsistent across different cognitive assessments (e.g., MMSE and ADAS-cog). Due to limited and inconsistent clinical evidence, RSV's therapeutic efficacy for AD or mild cognitive impairment (MCI) remains unproven, necessitating larger, well-powered clinical trials in diverse populations to evaluate its potential benefits. RSV holds promise as a potential therapeutic agent. Still, challenges such as poor bioavailability and rapid metabolism require optimized delivery systems and further research to establish clinical efficacy and optimal dosing. Show less

BACE1 promotes aggregation of β-amyloid in Alzheimer's patients' brains. MicroRNAs play roles in gene expression regulation. Furthermore, BACE1 is a target for microRNAs. There is a crosstalk between the peripheral and central immune systems in the etiology of Alzheimer's disease. This study investigates the alterations in expression of BACE1, along with miR-15a-5p and miR-19b-3p genes, in peripheral blood mononuclear cells (PBMCs) of late-onset Alzheimer's disease (LOAD) patients. The levels of BACE1 mRNA, miR-15a-5p, and miR-19b-3p were measured in PBMCs using a real-time quantitative PCR method. Cytoscape software was used to identify the putative target genes of these microRNAs. Significant increase in BACE1 levels (mean ± SD: 2.076 ± 0.5308), and decrease in both miR-15a-5p and miR-19b-3p expressions (0.3656 ± 0.1056 and 0.7296 ± 0.1933, respectively) were observed. Altered BACE1, miR-15a-5p, and miR-19b-3p expressions suggest novel indicators for early LOAD diagnosis. We illustrated target genes by which these microRNAs may regulate BACE1 expression. Show less

While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer's disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70 %) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability. 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

Osteosarcoma (OS) is an invasive and lethal malignancy showing a low 5 year survival rate, underscoring the need for identifying new therapeutic targets and their inhibitors to enhance prevention and treatment strategies. In this study, in vitro experiments including CCK-8 assay, anchorage-independent growth assays, and plate cloning assays were used to detect the anti-proliferation ability of natural compound tangeretin towards OS cells. An integrated approach was performed including WGCNA and network pharmacology to identify the key genes of tangeretin for the treatment of OS. Multigene diagnostic model, reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis along with molecular docking analysis were further conducted to validate the reliability of the targets obtained by bioinformatics methods. Single-cell and gene enrichment analyses were chosen to explore the mechanism of tangeretin in OS. Hub genes identified by the bioinformatics strategy included ABCC1, AKR1C3, BACE1, and CA12. RT-qPCR validation and molecular docking analysis confirmed that ABCC1 and BACE1 were the most likely potential targets. A multigene diagnostic model for OS demonstrated moderate accuracy of the hub genes. Single-cell sequencing results indicated that these two hub targets were closely related to OS and provided more potential mechanisms for targeting OS. Our research highlights the therapeutic potential of the natural compound tangeretin and its antineoplastic mechanisms in OS. It offers new insights into the molecular mechanisms of tangeretin, paving the way for the development of effective OS treatments. Show less

Millions of people worldwide are affected by neurodegenerative disorders (NDs), which include a broad range of clinical ailments that affect the brain or peripheral nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, etc. Neuronal cell death in NDs is often linked to oxidative stress; thus, antioxidant treatment can combat oxidative cell damage, and this strategy has been studied in neurodegenerative processes. Over the past 10 years, we have witnessed intense research activity on the biological potential of human monoamine oxidase (hMAO) inhibitors that have been associated with the prevention of oxidative stress and inflammation. These inhibitors have emerged as promising therapeutic agents, especially in the treatment of neurodegenerative diseases (NDs), where their core activity may help mitigate disease progression. An overview of the current state of numerous scaffolds, such as chromones, coumarins, chalcones, propargylamines, benzothiazoles, aminoisoquinolines, and the natural compounds, including ferulic acid, resveratrol, and chrysin, which combine antioxidant capability and hMAO inhibition is given in this review, with particular attention given to each scaffold's mechanism of action and structure-activity relationships (SARs), which are thoroughly discussed. Focusing on the dual mechanism of action, combining inhibition and antioxidant properties, as a potential therapy for neurodegenerative diseases, we have reviewed the different chemical classes of multi-targetdirected ligand (MTDL) inhibitors developed within this framework. Other central nervous system (CNS)-related enzymes, such as cholinesterases, carbonic anhydrases, and BACE-1, have also been explored as targets in the MTDL strategy. By understanding their biological activity, medicinal chemists can better comprehend biological activity and recommend more effective and specific ND treatments. Show less

Light therapy, using red and near-infrared (NIR) irradiation, is currently applied for the treatment of various neurodegenerative diseases, such as Alzheimer's disease (AD). Transcranial photobiomodulation therapy (tPBMT) can alleviate neurodegeneration, neuronal loss, and β-amyloid peptide plaque burden. Alternatively, potential early inhibition of oxidative stress, neuroinflammation, apoptosis, and amyloidogenic cellular pathways may constrain pathological changes with aging. In this research, we conduct an 808-nm tPBMT with a 30-day course of daily 1-hour sessions for mice and assess its influence on molecular mechanisms related to the potential onset of neurodegeneration. To comprehensively identify molecular mechanisms of tPBMT on the brain cells, the next-generation whole RNA sequencing of over 30,000 mRNA of the cortex and hippocampus of BALB/c mice is performed. After tPBMT, transcriptional alterations are found in 1,005 genes in the hippocampus and 1,482 genes in the cortex. Pathway-gene enrichment network analysis identifies genes associated with about 20 pathways of neurodegeneration, and a disease-gene network is constructed. Particularly, tPBMT alters the transcription and expression of the essential genes associated with oxidative stress (NF-κBIα, JUN, JUND, and PKC genes), inflammation (DOCK4/6, IL-1RAPL1, and TNFαIP6), and apoptosis (CASP3, TNFαIP6, AKT3, CDKN1A, CYP51, RASA2, and RESTAT). Additionally, 808-nm light modulates the main risk genes for AD (BACE1, BACE2, PSEN2, APH1B, GATA2, YY2, RELA, STAT3, JUN, JUND, ARNTL, CREB3L1, CELF2, E2F4, ELK3, and CEBPD), involved in APP processing supporting AD development. Moreover, the APP concentration is reduced after tPBMT. Hence, PBMT may help inhibit the development of different neurodegeneration types and maintain normal brain conditions. Show less

Microglia-mediated neuroinflammation plays a crucial role in memory and cognitive deficits and the development of early mild cognitive impairment (MCI) associated with Alzheimer's disease (AD). Paeoniflorin (PF) has been established as an effective antioxidant and anti-apoptotic agent. This study investigated the protective effects of PF on neuroinflammation, amyloidogenesis, and memory impairments in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a C57BL/6 J amnesic mouse model. In BV-2 microglial cells, PF treatment inhibited LPS-stimulated nitric oxide (NO) production, attenuated microglial overactivation, and suppressed the excessive release of inflammatory mediators (iNOS and COX-2) in a concentration-dependent manner. More crucially, PF regulated the LPS-stimulated phosphorylation of mitogen-activated protein kinases (MAPKs)-including p38, ERK, and JNK-while also suppressing NF-κB nuclear transport and inhibiting IκB-α phosphorylation. In the in vivo study, PF (10 or 20 mg/kg) treatment significantly improved spatial learning memory and cognitive function and ameliorated memory deficits. Furthermore, PF administration upregulated BDNF, p-CREB, Nrf2, and HO-1 expression, which are biomarkers of neuroprotective and antioxidant effects. This was accompanied by a reduction in markers of neuroinflammation (iNOS and COX-2), the inhibition of microglia and astrocytes overactivation, and decreased expression of amyloidogenic protein markers APP and BACE-1 in the hippocampus and cerebral cortex. Further, PF inhibited the LPS-promoted phosphorylation of MAPK signaling, thereby reducing the phosphorylation level of IκB-α and inhibiting NF-κB activation in the hippocampus and cerebral cortex. Our results suggest that PF confers neuroprotective effects in an LPS model of Alzheimer-associated MCI by regulating the Nrf2/HO-1/BDNF/CREB and APP/BACE-1/NF-κB/MAPK signaling pathways. Show less

Clinically, Alzheimer's disease (AD) is characterized by progressive cognitive decline due to neuronal and synaptic degeneration. Neurofilament light chain (NfL) and total tau (T-tau) reflect neurodegeneration, NfL putatively more related to white and T-tau to grey matter. This study examines how cerebrospinal fluid (CSF) neurodegeneration markers (T-tau, NfL or both) are correlated with synaptic markers and clinical progression. We included 331 individuals with (n = 212) and without (n = 119) pathological CSF Aβ42/40 ratios. Associations between CSF NfL, T-tau, and the synaptic biomarkers neurogranin and BACE1 were assessed using Pearson's correlation. Group differences in synaptic marker levels were evaluated using linear regression comparing individuals with isolated pathological T-tau, NfL, or both, versus biomarker-negative individuals. Clinical progression to MCI or dementia was assessed using a Cox proportional hazards model (n = 257; mean follow-up = 3.75 years). Linear regression and Cox proportional hazards models included age, sex, and dichotomized APOE-ε4 carriership as covariates. T-tau had a stronger correlation with neurogranin(r = 0.84) and BACE1(r = 0.73) than NfL(r = 0.51 and 0.48; p < 0.001). Group-wise comparisons confirmed this, showing that only individuals with pathological T-tau-alone or with NfL-had significantly higher synaptic marker levels (p < 0.001). Only the combination of pathological T-tau and NfL was associated with a significantly increased risk of clinical progression(HR=6.79; p < 0.001). These findings suggest that T-tau is more closely related to early synaptic dysfunction in AD than NfL. The combined elevation of both biomarkers, linked to greater clinical decline, supports a dual contribution of grey- and white matter degeneration to disease progression. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions of people worldwide, with its prevalence expected to rise in the coming years. Due to the complexity of AD and the intricate interplay among its pathological mechanisms, the development of multitarget-directed ligands (MTDLs) has emerged as a promising therapeutic strategy. These compounds could simultaneously modulate multiple pathogenic pathways. Specifically, cholinergic and amyloid mechanisms, implicated in the onset of the disease, are regulated by AChE and BACE1, respectively. Therefore, targeting both pathways offers substantial therapeutic potential for AD. Computational tools can be useful in the identification of potential MTDL for these enzymes, reducing both costs and time in the drug discovery process. This review explores the relevance of this approach in the research and development for novel AD therapies, highlighting ongoing efforts focused on the identification and development of MTDLs for AChE and BACE1 inhibition through in silico methods. Virtual screening was the most frequently applied technique for a fast selection of ligands based on their affinity for the enzymes of interest. The in silico ADMET prediction also appears with a technique that allows the screening of compounds with drug-likeness. Moreover, evidence suggests that combining multiple computational methods can effectively identify drug candidates with optimized properties for target modulation and brain bioavailability. Show less

Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration. Show less

This study aims to evaluate cognitive impairment utilizing the Montreal Cognitive Assessment (MoCA) scale, while also exploring the correlation between cognitive impairment and various serum biomarkers, including Brain-derived neurotrophic factor (BDNF), Beta Secretase-1 (BACE1), Vascular Endothelial Growth Factors (VEGF), Glial fibrillary acidic protein (GFAP), and Interleukin-1 (IL-1β) in adults living with epilepsy. In this study, 74 participants aged between 18 and 50 years, who were visiting neurology outpatient consultations, were included. The cognitive assessment was executed using the MoCA test. Serum levels of BDNF, BACE1, VEGF, GFAP, and IL-1β were evaluated through ELISA in patients with and without cognitive impairments. To determine the association between MoCA scores and the biomarkers, both Spearman and Pearson correlation analyses, as well as linear regression, were conducted. Among the 74 PWE, 61 exhibited cognitive impairment as determined by the MoCA assessment. Noteworthy alterations were detected across various MoCA subscales, encompassing visuospatial and executive functions, attention, language, abstraction, and delayed recall, with statistical significance established ( We conclude that adult PWE in India demonstrate a significant cognitive impairment. Further, our findings indicate that BDNF may serve as a potential biomarker for evaluating cognitive impairment in adult PWE. Further longitudinal, prospective and multi-center studies are required to confirm the same. Show less

β-Amyloid (Aβ) is generated from the amyloid precursor protein (APP) through sequential cleavage by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase, where BACE1 acting as the rate-limiting enzyme. Elevated BACE1 levels in the brains of Alzheimer's disease (AD) patients implicate that dysregulated BACE1 expression is crucial to AD pathogenesis. However, the underlying regulatory mechanisms remain unclear. Here, we identified that the G protein subunit β5 gene (Gnb5), a component of the G protein-coupled receptor (GPCR) signaling pathway, is significantly downregulated in both human AD patients and AD mouse models. Conditional knockout of Gnb5 in excitatory neurons resulted in cognitive impairments, whereas adeno-associated virus (AAV)-mediated overexpression of Gnb5 in the hippocampus ameliorated cognitive deficits and reduced Aβ deposition in 5xFAD mice. Mechanistically, we demonstrated that Gnb5 interacts with BACE1, modulating its expression and potentially influencing Aβ generation. We further identify the first tryptophan-aspartate domain (WD domain) of Gnb5 and the Ser81 residue as crucial for this regulation. Expression of this WD domain alone is sufficient to reduce Aβ deposition in 5xFAD mice, whereas a point mutation at Ser81 (S81L) abolishes this effect. Overall, our findings establish Gnb5 as a negative regulator of the BACE1-APP processing axis and unveil mechanistic insights into its role in Aβ-mediated AD pathogenesis. Show less