BACE1 Research Articles

Design, synthesis, in silico, and in vitro evaluation of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors.

Alzheimer's disease (AD) manifests as a progressive decline in cognitive function and mental behavior. Targeting two crucial enzymes associated with AD, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), in combination, holds promise for therapeutic breakthroughs. In this study, 40 derivatives of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide were designed based on prior research. These derivatives underwent synthesis and assessment for their inhibitory potential against AChE and BACE 1. ADME predictions indicated favorable physicochemical properties for these compounds. The findings offer novel avenues for exploring the dual inhibition of AChE and BACE 1 as a promising therapeutic strategy for AD.

A computational study of buckyballs as potential inhibitors of BACE1 in Alzheimer’s treatment

Alzheimer’s disease, marked by cognitive decline and memory loss, involves BACE1 in generating Aβ peptides, making it a key drug target. This study screened 129 buckyball ligands using molecular docking, identifying three promising compounds (4_C26_d3hc, 8_C20_Ih, and 16_C24_d6d) that fit within the BACE1 binding site. Molecular dynamics simulations highlighted thirteen BACE1 residues crucial for binding to buckyball ligands. The binding affinities of these ligands were also revealed via free energy perturbation (FEP), with 4_C26_d3hc demonstrating the greatest potential. This work lays the foundation for developing new BACE1 inhibitors using buckyball structures, offering a promising approach for Alzheimer’s therapy.

Significance of Gene Polymorphism and Gene Expression of BACE2 in Swedish Patients with Colorectal Cancer.

β-site amyloid precursor protein (APP) cleaving enzyme 2 (BACE2) cleaves APP which is ubiquitously expressed in a variety of cell types including cancer cells. BACE2 can process APP in several ways and appears to be involved in the pathogenesis of cancer. Our purpose was to assess the association of mRNA expression and genetic polymorphism of BACE2 in colorectal cancer (CRC) susceptibility and its association to clinicopathological factors in Swedish patients with CRC. A total of 720 CRC patients and 470 healthy controls were genotyped for BACE2 gene polymorphism rs2012050, using TaqMan single nucleotide polymorphism (SNP) assays based on polymerase chain reaction. Reverse transcription quantitative PCR was used to investigate the BACE2 gene expression in 192 CRC tissue and 181 paired normal tissue. Assessing clinicopathological factors, we noted that carrying of T allele in C/T and C/T+T/T was significantly associated with a protective role against disseminated cancer and higher lymph node status. Moreover, individuals carrying T/T genotype were significantly more likely to have poorly differentiated cancer. Follow-up data for patients in poorly differentiated cancer and the Kaplan-Meier analysis showed that the cancer-specific survival curves differed between C/C and C/T+T/T for the BACE2 gene polymorphism and that the carriers of the genotype C/C were associated with more favorable prognosis. We found no significant differences in the genotypic frequencies between the patients and healthy controls. BACE2 mRNA level was significantly 2.2-fold upregulated in CRC tissue when compared to noncancerous tissue. A higher BACE2 mRNA level was observed in smaller tumors and in rectal cancer when compared to colon cancer. In patients with CRC, our results indicate BACE2 rs2012050 as a useful potential predictor of poor differentiation, disseminated cancer and lymph node status and that the BACE2 mRNA expression is associated to tumor size and cancer location.

Exploring the molecular mechanisms underlying neuroprotective effect of ellagic acid in okadaic acid-induced Alzheimer's phenotype.

Pomegranate polyphenol ellagic acid has medicinal potential in neurodegenerative disorders. The advantageous effect of this polyphenol in improving cognition in okadaic acid (OA)-instigated murine model with unraveling some modes of its action was assessed. Rats received ICV okadaic acid (OA) and post-treated with oral ellagic acid for 3 weeks (25 and 100mg/kg/day). Cognition was analyzed in behavioral tasks besides assessment of oxidative, apoptotic, and inflammatory factors in addition to hippocampal histochemical analysis. Ellagic acid at a dose of 100mg/kg properly attenuated cognitive abnormalities in novel object recognition (NOR), Y maze, and Barnes maze tests. Additionally, ellagic acid diminished hippocampal changes of malondialdehyde (MDA), protein carbonyl, reactive oxygen species (ROS), glutathione (GSH), glutathione peroxidase, superoxide dismutase (SOD), apoptotic factors caspases 1 and 3, tumor necrosis factor α (TNFα), and acetylcholinesterase (AChE) and beta secretase 1 (BACE 1) besides reversal of AMP-activated protein kinase (AMPK) and hyperphosphorylated tau (p-tau). Moreover, lower glial fibrillary acidic protein (GFAP) and less injury of hippocampal CA1 pyramidal neurons were observed upon ellagic acid. To conclude, neuroprotective potential of ellagic acid was shown which is somewhat attributable to its reversal of oxidative, apoptotic, and neuroinflammatory events in addition to proper regulation of AMPK and p-tau.

Synthesis and Evaluation of Chloride-Substituted Ramalin Derivatives for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer's disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.

Edaravone N-benzyl pyridinium derivatives: BACE-1 inhibition, kinetics and in silico binding pose determination

BACE-1 plays a pivotal role in the production of β-amyloid (Aβ) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC50 = 44.10 µM - 123.70 µM) and obtained IC50 values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC50 = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC50 of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

Serum Beta-Secretase 1 Activity Is a Potential Marker for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Dementia: A Pilot Study.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

Canagliflozin Mitigated Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer's Disease in Mice: Role of AMPK/SIRT-1 Signaling Pathway in Modulating Neuroinflammation.

Sporadic Alzheimer's disease (SAD) represents a major health concern especially among elderly. Noteworthy, neuroinflammation and oxidative stress are highly implicated in AD pathogenesis resulting in enhanced disease progression. Moreover, most of the available anti-Alzheimer drugs have several adverse effects with variable efficacy, therefore new strategies, including agents with anti-inflammatory and antioxidant effects, are encouraged. Along these lines, canagliflozin (CAN), with its anti-inflammatory and anti-apoptotic activities, presents a promising candidate for AD treatment. Therefore, this study aimed to evaluate the therapeutic potential of CAN via regulation of AMPK/SIRT-1/BDNF/GSK-3β signaling pathway in SAD. SAD model was induced by intracerebroventricular streptozotocin injection (ICV-STZ;3mg/kg, once), while CAN was administered (10mg/kg/day, orally) to STZ-treated mice for 21 days. Behavioral tests, novel object recognition (NOR), Y-Maze, and Morris Water Maze (MWM) tests, histopathological examination, total adenosine monophosphate-activated protein kinase (T-AMPK) expression, p-AMPK, and silent information regulator-1 (SIRT-1) were evaluated. Furthermore, brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3β (GSK-3β), acetylcholinesterase (AChE), Tau protein, insulin-degrading enzyme (IDE), nuclear factor erythroid-2 (Nrf-2), interleukin-6 (IL-6), nuclear factor kappa-B-p65 (NFκB-p65), beta-site APP cleaving enzyme 1 (BACE-1), and amyloid beta (Aβ) plaque were assessed. CAN restored STZ-induced cognitive deficits, confirmed by improved behavioral tests and histopathological examination. Besides, CAN halted STZ-induced neurotoxicity through activation of p-AMPK/SIRT-1/BDNF pathway, subsequently reduction of GSK-3β, Tau protein, AChE, NFκB-p65, IL-6, BACE-1, and Aβ plaque associated with increased IDE and Nrf-2. Consequentially, our findings assumed that CAN, via targeting p-AMPK/SIRT-1 pathway, combated neuroinflammation and oxidative stress in STZ-induced AD. Thus, this study highlighted the promising effect of CAN for treating AD.

Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties.

Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer's disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein-huprine hybrid lead by hydroxy group removal-ring contraction-ring opening-ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC50 >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification.

Synthesis and Neurobehavioral Evaluation of a Potent Multitargeted Inhibitorfor the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) poses a significant health challenge worldwide, affecting millions of individuals, and projected to increase further as the global population ages. Current pharmacological interventions primarily target acetylcholine deficiency and amyloid plaque formation, but offer limited efficacy and are often associated with adverse effects. Given the multifactorial nature of AD, there is a critical need for novel therapeutic approaches that simultaneously target multiple pathological pathways. Targeting key enzymes involved in AD pathophysiology, such as acetylcholinesterase, butyrylcholinesterase, beta-site APP cleaving enzyme 1 (BACE1), and gamma-secretase, is a potential strategy to mitigate disease progression. To this end, our research group has conducted comprehensive in silico screening to identify some lead compounds, including IQ6 (SSZ), capable of simultaneously inhibiting the enzymes mentioned above. Building upon this foundation, we synthesized SSZ, a novel multitargeted ligand/inhibitor to address various pathological mechanisms underlying AD. Chemically, SSZ exhibits pharmacological properties conducive to AD treatment, featuring pyrrolopyridine and N-cyclohexyl groups. Preclinical experimental evaluation of SSZ in AD rat model showed promising results, with notable improvements in behavioral and cognitive parameters. Specifically, SSZ treatment enhanced locomotor activity, ameliorated gait abnormalities, and improved cognitive function compared to untreated AD rats. Furthermore, brain morphological analysis demonstrated the neuroprotective effects of SSZ, attenuating Aβ-induced neuronal damage and preserving brain morphology. Combined treatment of SSZ and conventional drugs (DON and MEM) showed synergistic effects, suggesting a potential therapeutic strategy for AD management. Overall, our study highlights the efficacy of multitargeted ligands like SSZ in combating AD by addressing the complex etiology of the disease. Further research is needed to elucidate the full therapeutic potential of SSZ and the exploration of similar compounds in clinical settings, offering hope for an effective AD treatment in the future.

Beta-Site APP-Cleaving Enzyme-1 Inhibitory Role of Natural Flavonoids in the Treatment of Alzheimer's Disease.

Alzheimer's Disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive function, including memory loss, reasoning difficulties, and disorientation. Its hallmark features include the formation of neurofibrillary tangles and neuritic plaques in the brain, disrupting normal neuronal function. Neurofibrillary tangles, composed of phosphorylated tau protein and neuritic plaques, containing amyloid-β protein (Aβ) aggregates, contribute to the degenerative process. The discovery of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in 1999 revolutionized our understanding of AD pathogenesis. BACE1 plays a crucial role in the production of Aβ, the toxic protein implicated in AD progression. Elevated levels of BACE1 have been observed in AD brains and bodily fluids, underscoring its significance in disease onset and progression. Despite setbacks in clinical trials of BACE1 inhibitors due to efficacy and safety concerns, targeting BACE1 remains a promising therapeutic strategy for early-stage AD. Natural flavonoids have emerged as potential BACE1 inhibitors, demonstrating the ability to reduce Aβ production in neuronal cells and inhibit BACE1 activity. In our review, we delve into the pathophysiology of AD, highlighting the central role of BACE1 in Aβ production and disease progression. We explore the therapeutic potential of BACE1 inhibitors, including natural flavonoids, in controlling AD symptoms. Additionally, we provide insights into ongoing clinical trials and available patents in this field, shedding light on future directions for AD treatment research.

A Bilingual Nanobiosensor for Cross‐Category Integrated Decoding of the Beta‐Site Amyloid Precursor Protein‐Cleaving Enzyme 1–Aβ Oligomer Signaling Pathway

Herein, a sequentially responsive peptide DNA bilingual nanobiosensor is developed, which allows integrated quantification of amyloid signaling pathway. In this system, upstream beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) protease and downstream Aβ oligomer (AβO) are designed as two inputs for the AND DNA logic gate. In the existence of both inputs, peptide substrate with aptamer can be sequentially cleaved, reporting electrochemical and fluorescence dual‐mode outputs. In comparison with conventional single protease activity assay based on peptide nanotechnology, this strategy permits accurate diagnosis of Alzheimer's disease (AD) from normal subjects. More importantly, it can achieve distinguished diagnosis between AD and type 2 diabetes mellitus patients. This bilingual nanobiosensor is successfully applied to detect BACE1 (1–100 U mL−1) and AβO (5–1000 pg mL−1) with limit of detections as low as 0.10 U mL−1 and 0.76 pg mL−1, respectively. Furthermore, this strategy inspires advanced nanobiosensors to target the activation of other signaling pathways, which are potential tools for future biology and medicine investigation.

MGST3 regulates BACE1 protein translation and amyloidogenesis by controlling the RGS4-mediated AKT signaling pathway

Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer's disease (AD). Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular ROS level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes (cysLTs), the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysLTs but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT (p-AKT) was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on p-AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway.

Anti-oxidant activity of coenzyme Q10 against AlCl3/D-galactose in albino rat induced cognitive dysfunctions: Behavioral, biochemical, and BACE-1/GSK-3β alterations.

The relationship between amyloid beta (Aβ) and oxidative stress (OS), both prominent factors in Alzheimer's disease-related neural degeneration, is deeply interconnected. The cleavage of the extracellular domain of Amyloid precursor protein (APP) and phosphorylating different substrates, respectively, the β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) and Glycogen synthase kinase-3-beta (GSK-3β) enzymes initiate the synthesis of Aβ, which causes cognitive deficits in AD. This study aimed to explore the protective potential of Coenzyme Q10 (CoQ10). It also sought to uncover any synergistic effects when combined with donepezil, an acetylcholinesterase inhibitor, in treating Alzheimer's disease in male albino rats, focusing on the modulation of the BACE-1/GSK-3β pathway. The experiment involved 70 rats categorized into different groups: control, donepezil alone, CoQ10 alone, AD-model, donepezil co-treatment, CoQ10 co-treatment, and CoQ10+donepezil combination. Various assessments, such as cholinesterase activity, oxidative stress, serum iron profile, Brain Derived Neurotrophic Factor (BDNF), Tau protein, β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), phosphatase and tensin homolog (Pten), and Glycogen synthase kinase-3-beta (GSK-3β), were conducted on behavioral and biochemical aspects. CoQ10 treatment demonstrated memory improvement, enhanced locomotion, and increased neuronal differentiation, mainly through the inhibition of the dual BACE-1/GSK-3β. These findings were substantiated by histological and immunohistological examinations of the hippocampus.

Navigating the Alzheimer's Treatment Landscape: Unraveling Amyloid-Beta Complexities and Pioneering Precision Medicine Approaches.

A variety of cutting-edge methods and good knowledge of the illness's complex causes are causing a sea change in the field of Alzheimer's Disease (A.D.) research and treatment. Precision medicine is at the vanguard of this change, where individualized treatment plans based on genetic and biomarker profiles give a ray of hope for customized therapeutics. Combination therapies are becoming increasingly popular as a way to address the multifaceted pathology of Alzheimer's by simultaneously attacking Aβ plaques, tau tangles, neuroinflammation, and other factors. The article covers several therapeutic design efforts, including BACE inhibitors, gamma- secretase modulators, monoclonal antibodies (e.g., Aducanumab and Lecanemab), and anti- Aβ vaccinations. While these techniques appear promising, clinical development faces safety concerns and uneven efficacy. To address the complicated Aβ pathology in Alzheimer's disease, a multimodal approach is necessary. The statement emphasizes the continued importance of clinical trials in addressing safety and efficacy concerns. Looking ahead, it suggests that future treatments may take into account genetic and biomarker traits in order to provide more personalized care. Therapies targeting Aβ, tau tangles, neuroinflammation, and novel drug delivery modalities are planned. Nanoparticles and gene therapies are only two examples of novel drug delivery methods that have the potential to deliver treatments more effectively, with fewer side effects, and with better therapeutic results. In addition, medicines that target tau proteins in addition to Aβ are in the works. Early intervention, based on precise biomarkers, is a linchpin of Alzheimer's care, emphasizing the critical need for detecting the disease at its earliest stages. Lifestyle interventions, encompassing diet, exercise, cognitive training, and social engagement, are emerging as key components in the fight against cognitive decline. Data analytics and art are gaining prominence as strategies to mitigate the brain's inflammatory responses. To pool knowledge and resources in the fight against Alzheimer's, international cooperation between scientists, doctors, and pharmaceutical companies is still essential. In essence, a complex, individualized, and collaborative strategy will characterize Alzheimer's research and therapy in the future. Despite obstacles, these encouraging possibilities show the ongoing commitment of the scientific and medical communities to combat A.D. head-on, providing a glimmer of hope to the countless people and families touched by this savage sickness.

Inhibition of BACE1 affected both its Aβ producing and degrading activities and increased Aβ42 and Aβ40 levels at high-level BACE1 expression

The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant β-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic pathway. In addition, BACE1 as an amyloid degrading enzyme (ADE), cleaves Aβ to produce the C-terminally truncated non-toxic Aβ fragment Aβ34 which is an indicator of amyloid clearance.Here, we analyzed effects of BACE1 inhibitors on its opposing enzymatic functions, i.e., amyloidogenic (Aβ producing) and amyloidolytic (Aβ degrading) activities, using cell culture models with varying BACE1/APP ratios. Under high level BACE1 expression, low-dose inhibition unexpectedly yielded a two-fold increase in Aβ42 and Aβ40 levels. The concomitant decrease in Aβ34 and secreted APPβ levels suggested that the elevated Aβ42 and Aβ40 levels were due to the attenuated Aβ degrading activity of BACE1. Notably, the amyloidolytic activity of BACE1 was impeded at lower BACE1 inhibitor concentrations compared to its amyloidogenic activity, thereby suggesting that the Aβ degrading activity of BACE1 was more sensitive to inhibition than its Aβ producing activity. Under endogenous BACE1 and APP levels, “low-dose” BACE1 inhibition affected both the Aβ producing and degrading activities of BACE1, i.e., significantly increased Aβ42/Aβ40 ratio and decreased Aβ34 levels, respectively. Further, we incubated recombinant BACE1 with synthetic Aβ peptides and found that BACE1 has higher affinity for Aβ substrates over APP. In summary, our results suggest that stimulating BACE1’s ADE activity and halting Aβ production without decreasing Aβ clearance could still be a promising therapeutic approach with new, yet to be developed, BACE1 modulators.

Network Models of BACE-1 Inhibitors: Exploring Structural and Biochemical Relationships.

This study investigates the clustering patterns of human β-secretase 1 (BACE-1) inhibitors using complex network methodologies based on various distance functions, including Euclidean, Tanimoto, Hamming, and Levenshtein distances. Molecular descriptor vectors such as molecular mass, Merck Molecular Force Field (MMFF) energy, Crippen partition coefficient (ClogP), Crippen molar refractivity (MR), eccentricity, Kappa indices, Synthetic Accessibility Score, Topological Polar Surface Area (TPSA), and 2D/3D autocorrelation entropies are employed to capture the diverse properties of these inhibitors. The Euclidean distance network demonstrates the most reliable clustering results, with strong agreement metrics and minimal information loss, indicating its robustness in capturing essential structural and physicochemical properties. Tanimoto and Hamming distance networks yield valuable clustering outcomes, albeit with moderate performance, while the Levenshtein distance network shows significant discrepancies. The analysis of eigenvector centrality across different networks identifies key inhibitors acting as hubs, which are likely critical in biochemical pathways. Community detection results highlight distinct clustering patterns, with well-defined communities providing insights into the functional and structural groupings of BACE-1 inhibitors. The study also conducts non-parametric tests, revealing significant differences in molecular descriptors, validating the clustering methodology. Despite its limitations, including reliance on specific descriptors and computational complexity, this study offers a comprehensive framework for understanding molecular interactions and guiding therapeutic interventions. Future research could integrate additional descriptors, advanced machine learning techniques, and dynamic network analysis to enhance clustering accuracy and applicability.

Network pharmacology study on fermented soybeans for the prevention of Alzheimer's disease in older individuals.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the disruption of synaptic communication among millions of neurons. Recent research has highlighted the potential therapeutic effectiveness of natural polyphenolic compounds in addressing AD. Soybeans are abundant in polyphenols, and their polyphenolic composition undergoes significant alteration through fermentation by Eurotium cristatum. Through comprehensive database searches, we identified active components within fermented soybean polyphenols and genes associated with AD. Subsequently, we utilized Venn diagrams to analyze the overlap between AD-related genes and these components. Furthermore, we visualized the network between intersecting targets and proteins using Cytoscape software. The anti-AD effects of soybeans were further explored through comprehensive analysis, including protein-protein interaction analysis, pathway enrichment analysis, and molecular docking studies. Our investigation unveiled 6-hydroxydaidzein as a major component of fermented soybean polyphenols, shedding light on its potential therapeutic significance in combating AD. The intersection between target proteins of fermented soybeans and disease-related targets in AD comprised 34 genes. Protein-protein interaction analysis highlighted key potential targets, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycogen synthase kinase 3 beta (GSK3B), amyloid precursor protein (APP), cyclin-dependent kinase 5 (CDK5), and beta-site APP cleaving enzyme 1 (BACE1). Molecular docking results demonstrated a robust binding effect between major components from fermented soybeans and the aforesaid key targets implicated in AD treatment. These findings suggest that fermented soybeans demonstrate a degree of efficacy and present promising prospects in the prevention of AD.

Targeting key players in Alzheimer’s disease: bioactive compounds from Moringa oleifera, Desmodium gangeticum, and Centella asiatica as potential therapeutics

Alzheimer’s Disease (AD) is one of the critical reasons for dementia around the world, with a huge number of cases being reported every year. The breakdown of Amyloid Precursor Protein (APP) plays a crucial role in AD development. The Beta-site APP Cleaving Enzyme 1 (BACE1) is a highly significant proteolytic enzyme found to be critically involved in the APP breakdown process and generates beta-amyloid plaques in the extracellular neuronal membrane. In this study, we have used natural compounds with cognitive and neuroprotective activities from three plants, Centella asiatica, Moringa oleifera, and Desmodium gangeticum to inhibit the activity of BACE1. We have identified nine compounds out of 73 compounds filtered out from the three plants showing high affinity with the catalytic dyad region of BACE1 through molecular docking studies. Interestingly, the 200 ns molecular dynamics simulation study further confirmed the stability of the complexes formed between 9 compounds and the BACE1 protein. Furthermore, the free energy calculations also revealed these complexes possess favorable energies. Astilbin, Delphinidin 3-glucoside, and kaempferol 7-O-glucoside showed good binding affinity and structural stability when compared to other compounds and the control CNP520. Following a preliminary screening, the Astilbin compound was chosen based on the grounds of binding affinity, ADMET Properties, Hbond formation, Molecular Dynamic simulation, and MM-PBSA studies. A subsequent 1microsecond molecular dynamics simulation was conducted for the Astilbin complex. Through microsecond simulation, it was found that Astilbin alters BACE1's behavior and induces conformational rearrangements. Thus, this study opens a gateway to inhibit the activity of BACE1 protein through Astilbin thereby disclosing the possibility of managing Alzheimer’s Disease. Communicated by Ramaswamy H. Sarma

Multicolor, Cell-Impermeable, and High Affinity BACE1 Inhibitor Probes Enable Superior Endogenous Staining and Imaging of Single Molecules.

The prevailing but not undisputed amyloid cascade hypothesis places the β-site of APP cleaving enzyme 1 (BACE1) center stage in Alzheimer's Disease pathogenesis. Here, we investigated functional properties of BACE1 with novel tag- and antibody-free labeling tools, which are conjugates of the BACE1-inhibitor IV (also referred to as C3) linked to different impermeable Alexa Fluor dyes. We show that these fluorescent small molecules bind specifically to BACE1, with a 1:1 labeling stoichiometry at their orthosteric site. This is a crucial property especially for single-molecule and super-resolution microscopy approaches, allowing characterization of the dyes' labeling capabilities in overexpressing cell systems and in native neuronal tissue. With multiple colors at hand, we evaluated BACE1-multimerization by Förster resonance energy transfer (FRET) acceptor-photobleaching and single-particle imaging of native BACE1. In summary, our novel fluorescent inhibitors, termed Alexa-C3, offer unprecedented insights into protein-protein interactions and diffusion behavior of BACE1 down to the single molecule level.