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Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. Show less

Neuroinflammation plays a key role in Alzheimer's disease (AD), but the actions of microglial mediators may vary across stages of amyloid-beta (Aβ) pathology. While drugs targeting brain immune responses are advancing to clinical trials, biomarkers to monitor their effects are lacking. This study investigated proteins expressed by activated microglia in three mouse models of Aβ pathology and α-synuclein, both during disease progression and after treatment, to evaluate their potential as in vivo biomarkers. Immunofluorescent staining was performed on cortical sections from App 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

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

Despite emerging therapeutic options, Alzheimer´s disease (AD) management remains suboptimal due to multimodal pathogenesis. We investigated curcumin-donepezil combination therapy, as curcumin demonstrates antioxidant, anti-inflammatory, and anti-amyloidogenic properties that may complement donepezil's cholinesterase inhibition. We employed the elav-Gal4/UAS-hAPP-BACE-1 Drosophila melanogaster model alongside molecular docking simulation and ADMET prediction to evaluate curcumin-donepezil combination versus monotherapy. Fruit flies received the treatment regimen, and were tested for survival, memory performance, and biochemical markers, including BACE-1 activity and oxidative stress parameters. Combination therapy significantly improved survival rates and memory performance compared to individual treatment. The combination effectively modulated multiple AD-related pathways, demonstrating reduced BACE-1 activity and decreased oxidative stress markers. Molecular docking confirmed favorable drug interactions, and ADMET profiles supported therapeutic viability. Curcumin-donepezil combination therapy shows promise as a multi-target approach for AD management. However, translation to clinical applications requires validation in higher-order models and human trials. 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

The dysregulation of long-chain noncoding RNAs (lncRNAs) causes several complex human diseases including neurodegenerative disorders across the globe. This study aimed to investigate lncRNA expression profiles of Withania somnifera (WS)-treated human neuroblastoma SK-N-SH cells at different timepoints (3 & 9 h) and concentrations (50 & 100 µg/mL) using RNA sequencing. Differential gene expression analysis showed a total of 4772 differentially expressed lncRNAs, out of which 3971 were upregulated and 801 were downregulated compared to controls. Differential gene expression was observed in dose-dependent (30 upregulated, 25 downregulated, 100 µg/mL 3 h vs. 50 µg/mL 3 h; 36 upregulated, 247 downregulated, 100 µg/mL 9 h vs. 50 µg/mL 9 h) and temporal kinetics (79 upregulated, 64 downregulated, 50 µg/mL 9 h vs. 50 µg/mL 3 h; 22 upregulated, 200 downregulated, 100 µg/mL 9 h vs. 100 µg/mL 3 h). Enrichment analysis showed that modulated lncRNAs were mainly implicated in GPCR ligand binding, HDACs and HATs histones, cellular senescence, cell cycle and post-translational protein modifications. Dysregulated lncRNAs upon WS treatment included BACE1-AS, MALAT1, SNHG1, HOTAIR, MEG3, BDNF-AS, and SHANK2-AS1 which are potential biomarkers in several neurodegenerative diseases. Co-expression analysis revealed that genes such as HMOX1, CHGB, SLC7A11, NOS1, KCNJ and NPY2R may be important in neurodegenerative disorders. Taken together, our results indicated that WS treatment modulated several differentially expressed lncRNAs with putative regulatory potential in various neurodegenerative disorders. To the best of our knowledge, the lncRNA regulome that elicits the health-beneficial effects of WS has not been delineated thus far. 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

Attention-deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder worldwide. To improve treatment strategies against ADHD a better understanding of underlying pathophysiology is required. Spontaneously hypertensive rats (SHR) from the strain SHR/NCrl are a suitable rodent model of ADHD. Here we compared the gene expression in the brains of SHR/NCrl strain to that of other genetically related hypertensive and normotensive rat strains that do not show an ADHD phenotype. In addition, the impact of physical activity on genes that display such differences was also addressed because high physical activity is one non-pharmacological option to cure ADHD symptoms. RNA was isolated from the medulla oblongata, the olfactory bulb, and the cortex. Gene expression was analyzed by qRT-PCR. The cortical expression of GLUT1 was also analyzed by Western Blot. Physical activity was improved by free access to running wheels for six months. Female rats were used in this study and sacrificed at the age of 7.5 months. The results show that gene expression in SHR/NCrl differs from other SHR strains in the olfactory bulb, medulla oblongata, and the cortex. Main differences were obtained for 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

Aluminum oxide nanoparticles (Al₂O₃NPs) are used across industrial and consumer sectors, raising concerns about their potential neurotoxic effects. Despite growing application, the mechanisms underlying Al₂O₃NP-induced neurodegeneration remain poorly understood. This study investigated the mechanistic pathways of Al₂O₃NP neurotoxicity in adult male Sprague-Dawley rats exposed intraperitoneally to 15, 30, or 60 mg/kg Al₂O₃NPs for 60 days. Comprehensive analyses included hematological profiling, serum biochemistry, oxidative stress markers (MDA, Nrf2/Keap1), neurotransmitter assays (dopamine, acetylcholine, AChE), quantitative PCR of APP, BACE1, and BDNF, inductively coupled plasma spectroscopy for brain aluminum levels, histopathology, immunohistochemistry (caspase-3, BCL2), and ultrastructural examination by transmission electron microscopy. Al₂O₃NP exposure induced dose-dependent anemia, disrupted iron and calcium homeostasis, and triggered oxidative stress, evidenced by elevated MDA and suppressed Nrf2/Keap1 signaling. Neurochemical analyses revealed marked dopamine and acetylcholine depletion alongside diminished AChE activity. Molecular assays showed significant upregulation of amyloidogenic markers (APP, BACE1) and severe BDNF suppression, indicating impaired neurotrophic support. Brain histopathology revealed progressive neuronal shrinkage, Purkinje cell loss, astrogliosis, and perivascular edema, while immunohistochemistry demonstrated heightened caspase-3 activation and reduced BCL2 expression. TEM confirmed ultrastructural axonal degeneration, demyelination, and necrotic neuronal profiles. Notably, aluminum bioaccumulation increased 116-fold at the highest dose, tightly correlating with neurodegeneration severity. These findings demonstrate that subchronic Al₂O₃NP exposure promotes neurodegeneration via a multifaceted oxidative stress mechanism, activating the amyloidogenic pathway, synaptic dysfunction, neurotrophic impairment, and apoptosis. This work underscores the urgent need for rigorous safety assessments of nanoparticle exposure in biomedical and environmental settings. 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

Alzheimer's disease (AD) is an age-associated neurodegenerative disease marked by progressive cognitive deterioration and beta-amyloid (Aβ) protein buildup, which currently lacks therapeutic interventions to decelerate its pathogenesis. The M1 muscarinic acetylcholine receptor (mAChR) is integral to synaptic plasticity and memory processes and has emerged as a critical target for ameliorating AD-associated cognitive deficits. Although M1 mAChR agonists have pro-cognitive potential, their clinical application is limited by significant cholinergic side effects. Our recent findings demonstrate that VU0486846, an M1 mAChR positive allosteric modulator (PAM) devoid of cholinergic toxicity, exhibits therapeutic benefits in a female APPswe/PSEN1ΔE9 (APP/PS1) Alzheimer's disease mouse model. This compound reversed memory deficits, alleviated anxiety-like behaviours, reduced Aβ pathology, and attenuated neuroinflammation in female mice. However, its therapeutic potential in male AD models remains to be fully characterized. In this study, we find that VU0486846 treatment restored cognitive function in male APP/PS1 mice, as evidenced by improved performance in the novel object recognition and Morris water maze tasks, and reduced anxiety-like behaviours in the open field test. VU0486846 ameliorates impaired autophagy signaling in the hippocampus, however, it does not alter hippocampal Aβ oligomer or plaque burden, despite decreasing BACE1 expression. These findings suggest that VU0486846 exerts behavioural and cognitive benefits via Aβ-independent mechanism(s). Collectively, this study highlights the therapeutic potential of VU0486846 in modulating AD pathophysiology, albeit via sex-specific signaling pathways. 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 is a progressive, irreversible, neurodegenerative disease, i.e., characterized by the presence of amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neural damage, etc. β-amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibition is a promising avenue for slowing AD progression. In a rate-limiting step, BACE-1 cleaves the amyloid precursor protein (APP) into soluble amyloid precursor protein β (sAPPβ) and a membrane-bound C-terminal fragment called C99. γ-secretase processes C99, resulting in neurotoxic amyloid β (Aβ). Selective and potent BACE-1 inhibitors offer promising therapeutic avenues for Alzheimer's disease. While BACE-1 inhibitors have shown significant assurance as potential treatments for Alzheimer's disease, many early compounds struggled to advance clinically due to poor brain penetration, limited selectivity, and unwanted side effects. Over the last two decades, substantial progress has been made in the development of BACE-1 inhibitors, leading to the emergence of diverse structural frameworks such as aminohydontoins, dihydropyridines, pyrimidines, and iminohydantoins, and fused heterocycles. This review provides an in-depth analysis of the synthetic strategies employed. It emphasizes the structure-activity relationship (SAR) trends that have guided their optimization and the crystal structure of the enzyme used in the inhibition study. Show less

Sjogren's syndrome (SS) is considered as a chronic, autoimmune disorder, that can present with various manifestations both intra and extra-glandular. Cognitive dysfunction is pivotal in recognizing neurological complications in SS. A study involving 44 SS cases and 37 controls was conducted to evaluate cognitive dysfunction further. Participants underwent multiple cognitive tests and blood tests for evaluation. Also, the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), Interleukin 6 (IL-6), total antioxidant capacity (TAC), nitric oxide (NO), and malondialdehyde (MDA) serum levels were measured. Multiple analyses were done by PRISM 10 and SPSS 22. The MoCA and SDLT scores were lower in Sjogren patients (P < 0.001). Serum BACE1, IL-6, NO, TAC, and MDA did not statistically vary in the SS patients. The only variables varied by medication therapy with methotrexate (MTX), hydroxychloroquine (HCQ), and prednisone were WBC count (P = 0.03) and triglyceride levels (in MTX and HCQ, P = 0.04), with no effect on neurocognitive factors. IL-6 was strongly correlated with the duration of symptoms (r = 0.99, P-value < 0.001). BACE1 had a positive correlation with IL-6 level (r = 0.4, P-value = 0.027). SS patients demonstrated significantly lower performance in neurocognitive tests, while BACE1 and inflammatory markers were not altered. This indicates that cognitive decline in SS is present but the mechanism still requires further evaluation. MTX, HCQ, and Prednisone use did not alter neurocognitive factors. Important correlations were found between hematological and cognitive tests in this study which provides new insights in the field of SS. Show less

Alzheimer's disease poses a serious global health challenge, and there is an urgent need for novel therapeutic agents, as existing drugs have limited efficacy and notable adverse effects. Chromenones, known for their diverse biological activities, have emerged as promising drug candidates for AD treatment due to their capacity to target multiple enzymes. In this study, investigated the chromenone derivative 8-methoxypsoralen (8-MOP) as a potential multi-target inhibitor of key AD targets, highlighting the importance of the scaffold in target-based drug design. 8-MOP, a phytochemical extracted and isolated from parsley leaves, was utilized to synthesize new derivatives, which were then screened against enzymes involved in AD progression (BACE1, AChE, BuChE) and targets involved in oxidative pathways (DPPH, NO). In support of the Among the synthesized compounds, Show less

Accurate and generalizable prediction of drug-target interactions (DTIs) remains a critical challenge for drug discovery, particularly when addressing underexplored targets and compounds. Recent advances in graph neural networks and large-scale pre-trained models offer new opportunities to capture rich structural and functional features essential for DTI prediction while enhancing the generalization ability. We present GS-DTI, a graph structure-based DTI prediction framework that integrates molecular graph transformers, protein language models, and protein tertiary structure. Our method achieved robust and interpretable DTI predictions. GS-DTI extracts drug features from SMILES-derived molecular graphs using a knowledge-guided pre-trained transformer, while protein features are derived from both sequence and predicted 3D structure for comprehensive representation. A multi-task loss function equipped with contrastive learning is adopted to enhance generalization and functional interpretability. Extensive experiments on the benchmarks and challenging cross-domain settings demonstrate that GS-DTI achieves state-of-the-art performance. Notably, our model improves the MCC by over 10% compared to previous methods in the drug-target pair cold start test. The model can pinpoint the binding pockets of the targets, offering robust interpretability, and case studies show GS-DTI's promising potential in virtual screening for new candidate drugs of BACE1. The GS-DTI source code and processed datasets are available at https://github.com/purvavideha/GSDTI. All experimental data are derived from public sources. 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