BACE1 Research Articles

Advancements in autophagy perturbations in Alzheimer's disease: Molecular aspects and therapeutics.

Emerging evidences suggest that autophagy, a key cellular process responsible for degrading and recycling damaged organelles and proteins, plays a crucial role in maintaining neuronal health. Dysfunctional autophagy has been linked to the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of misfolded proteins and cellular debris. Molecular mechanisms underlying autophagy dysfunction in AD involve amyloid-beta (Aβ) and tau accumulation, neuroinflammation, mitochondrial dysfunction, oxidative stress and endoplasmic reticulum stress. Disrupted signaling pathways such as TRIB3, Nmnat and BAG3 that regulate key processes like autophagosome initiation, lysosome function, and protein homeostasis also play a crucial role in the pathogenesis. Restoration of autophagy by modulating these molecular and signaling pathways may be an effective therapeutic strategy for AD. Studies have found few drugs targeting autophagy dysregulation in AD. These drugs include metformin that has been found to modulate the expression of TRIB3 for autophagy regulation. Another drug, resveratrol has been reported to augment the activity of Nmnat thus, increases autophagy flux. BACE1 and mTOR inhibitors like arctigenin, nilvadipine and dapagliflozin were also found to restore autophagy. This study elaborates recent advances in signaling and molecular pathways and discusses current and emerging therapeutic interventions targeting autophagy dysfunction in AD.

Meroterpenoids from Terrestrial and Marine Fungi: Promising Agents for Neurodegenerative Disorders—An Updated Review

Background: Meroterpenoids represent a remarkably diverse class of natural secondary metabolites, some of which are synthesized via terpenoid biosynthetic pathways. Over the past ten years, these compounds have gained interest because of their wide range of biological activities, such as anti-cholinesterase, COX-2 inhibitory, antibacterial, antiviral, antidiabetic, antioxidant, anti-inflammatory, antineoplastic, and cardioprotective properties. This review aims to consolidate the recognized neuroprotective effects of meroterpenoids from marine and terrestrial fungi. Methods: Data compiled from several databases, including PubMed, Science Direct, Scopus, and Google Scholar, include articles published since 2000 using keywords such as “neuroprotective”, “fungi”, “mushroom”, “marine sponge”, “neurodegeneration”, and “dementia” in connection with “meroterpenoids”. Results: Meroterpenoids modulate different cell signaling pathways and exhibit different and often combined mechanisms of action to ameliorate neuronal damage and dysfunction. Reported activities include anti-cholinesterase, antioxidant, BACE1 inhibition, and anti-inflammatory activities, all of which have potential in the treatment of dementia associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Conclusions: Meroterpenoids have the potential to be developed as effective tools for neuropathological diseases. Ongoing research to elucidate the various neuroprotective pathways remains essential and requires further investigation.

Natural Compounds for Alzheimer's Prevention and Treatment: Integrating Selformer-Based Computational Screening with Experimental Validation

BackgroundThis study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict natural compounds (NCs) with potential in Alzheimer's disease (AD) treatment. The NCs were identified based on activity related to seven AD-specific genes, including acetylcholinesterase (AChE), amyloid precursor protein (APP), beta-secretase 1 (BACE1), and presenilin-1 (PSEN1). MethodsWe implemented a computational pipeline using SELFormer and deep learning techniques, conducted optimal clustering and quantitative structure-activity relationship (QSAR) analyses, and performed a uniform manifold approximation and projection (UMAP) to categorize compounds based on bioactivity levels. Molecular docking analysis was carried out on selected compounds. To validate the computational predictions, we conducted in vitro studies using nerve growth factor (NGF)-differentiated PC12 cells. Finally, we mapped the relationships between food sources containing the identified compounds and their target proteins. ResultsOptimal clustering analysis revealed five distinct groups of NCs, while QSAR analysis highlighted variations in molecular properties across clusters. The UMAP projection identified 17 highly active NCs (pIC50>7). Molecular docking analysis showed that cowanin, β-caryophyllene, and L-citronellol demonstrated decreased binding energy across target proteins. In vitro studies confirmed significant biological activities of these compounds, including increased cell viability, decreased AChE activity, reduced lipid peroxidation and tumor necrosis factor (TNF)-α mRNA expression, and increased brain-derived neurotrophic factor (BDNF) mRNA expression compared to the control. The study also identified natural sources of these compounds, such as anatidae, mangosteen, and celery, providing insights into potential dietary interventions. ConclusionThis integrated computational and experimental approach offers a promising framework for identifying potential NCs for AD treatment. The results contribute to exploring effective therapeutic strategies against AD.

Exploring the Diverse Therapeutic Applications of 1, 3-Thiazine: A Comprehensive Review

Thiazine, a six-membered heterocycle containing nitrogen and sulfur atoms, is of paramount importance due to its diverse biological functions and broad therapeutic effects. The pharmacological attributes of 1,3-thiazine span a wide range of activities, including antileukemic, antimycobacterial, anti-inflammatory, sedative, hypnotic, anti-influenza, antituberculosis, melanogenesis inhibition, BACE1 inhibition (with anti-Alzheimer's potential), growth promotion, neuroprotective, and anticonvulsant properties. Consequently, novel synthetic methodologies and the design of new 1,3-thiazine derivatives are significantly influenced by recent research findings. This comprehensive review explores both in vivo and in vitro preclinical studies on the biomedical and therapeutic applications of 1,3-thiazine, highlighting its extensive medical relevance. It is anticipated that derivatization strategies for 1,3-thiazine will open new avenues for the development of innovative biological agents. This review aims to engage researchers, stimulating the creation of promising new treatments and preventive measures for various diseases.

Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold.

Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived N-amidinopyrrolidine scaffold. The initially synthesized derivative 7a showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure-activity relationship studies showed that introducing a substituent at the meta position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative 12f. In contrast, substituents at the para position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2S,4R)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors.

MiR-32533 Reduces Cognitive Impairment and Amyloid-β Overload by Targeting CREB5-Mediated Signaling Pathways in Alzheimer's Disease.

MicroRNAs (miRNAs) are associated with amyloid-β (Aβ)dysmetabolism, a pivotal factor in the pathogenesis of Alzheimer's disease (AD). This study unveiled a novel miRNA, microRNA-32533 (miR-32533), featuring a distinctive base sequence identified through RNA sequencing of the APPswe/PSEN1dE9 (APP/PS1) mouse brain. Its role and underlying mechanisms were subsequently explored. Bioinformatics and confirmatory experiments revealed that miR-32533 had a novel 23-base sequence with minimal coding potential, functioning within the Drosha ribonuclease III (Drosha)/Dicer 1, ribonuclease III (Dicer)-dependent canonical pathway and identifiable via northern blot. miR-32533 was abundantly brain-distributed and downregulated in diverse AD-related models, including APP/PS1 andfive familial AD (5×FAD) mouse brains and AD patient plasma. Overexpression or inhibition of miR-32533 led to improvements or exacerbations in cognitive dysfunction, respectively, by modulating Aβproduction, apoptosis, oxidation, and neuroinflammation through targeting cAMP-responsive element binding protein 5(CREB5), which interacted with α disintegrin and metalloproteinase 10(ADAM10), beta-site amyloid precursor protein cleaving enzyme 1(BACE1), and presenilin 1 (PS1) promoters, thereby enhancing Aβ production through BACE1 and PS1 upregulation while suppressing non-amyloidogenic amyloid precursor protein (APP) processing via ADAM10 downregulation. Furthermore, modulation of the miR-32533/CREB5 axis ameliorated or worsened cognitive impairment by inhibiting or amplifying Aβ overproduction through the BACE1-involved amyloidogenic and ADAM10-involved non-amyloidogenic pathways. Overall, the findings suggest miR-32533 as a regulator of Aβ metabolism, oxidative stress, and neuroinflammation, establishing the miR-32533/CREB5 signaling pathways as potential therapeutic targets for combating Aβ accumulation and cognitive deficits in AD.

Green magnetically separable molluscicide Ba–Ce–Cu ferrite/TiO2 nanocomposite for controlling terrestrial gastropods Monacha Cartusiana

The increasing economic damage caused by terrestrial gastropods, especially the Monacha cartusiana (M. cartusiana) land snail, to the agricultural sector requires a diligent and continuous search for new materials and alternatives for the control operations. In this piece of work, a magnetically separable molluscicide with high effectiveness green Barium–Cerium–Copper ferrite/TiO2 (Ba–Ce–CuFO/TiO2) nanocomposite was greenly prepared using Eichhornia plant aqueous extract and characterized using different techniques. The green Ba–Ce–CuFO/TiO2 nanocomposite was applied as an aspect of the attempts to search for new active substances that would have a potential toxic effect against M. cartusiana. Laboratory toxicity evaluations by leaf dipping and contact methods showed LC50 values of 1218.79 and 289.19 ppm, respectively. Analysis of biochemical variables as a bio response indicator showed a noticeable increase in the values of aspartate transaminase (AST) and alanine transaminase (ALT) relative to the control, while the decrease was characteristic for alkaline phosphatase (ALP) and total protein (TP) other variables when the animals were treated with LC50 value. The histopathological examination was performed on both the muscular foot and the digestive gland, or what is known as the hepatopancreas, which showed enlarged lumens and damaged digestive cells, in addition to destructed digestive tubes, the existence of pyknotic nuclei, and hematocyte infiltration. Foot histopathology showed ruptured epithelial cells, deep folds, and empty spaces when animals were treated with our target nanocomposite LC50 value. Application under natural field conditions through the bait technique showed a significant satisfactory population diminution after 14 days of exposure, as the mean percentage of diminution was 72.2% compared to the recommended pesticide Neomyl SL 20%, which poses a 74.27% reduction. Built on the above, we recommend further studies of the usage of green Ba–Ce–CuFO/TiO2 nanocomposite, and the introduction of such nanocomposite in gastropod control operations to reduce losses in the agricultural sector in general.

Traumatic brain injury causes early aggregation of beta-amyloid peptides and NOTCH3 reduction in vascular smooth muscle cells of leptomeningeal arteries

Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer’s-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated. Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA).These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ1-40/42, Aβ1-16, and β-secretase-derived fragment (βCTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of Aβ1-40/42 peptides were also observed in the leptomeningeal arteries of young TBI patients. These pathological changes also included higher β-secretase (BACE1) when compared to α-secretase A Disintegrin And Metalloprotease 10 (ADAM10) expression in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased βCTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.

Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer's-related phenotypes.

Interferon-induced transmembrane protein 3 (IFITM3) modulates γ-secretase in Alzheimer's Disease (AD). Although IFITM3 knockout reduces amyloid β protein (Aβ) production, its cell-specific effect on AD remains unclear. Single nucleus RNA sequencing (snRNA-seq) was used to assess IFITM3 expression. Adeno-associated virus-BI30 (AAV-BI30) was injected to reduce IFITM3 expression in the cerebrovascular endothelial cells (CVECs). The effects on AD phenotypes in cells and AD mice were examined through behavioral tests, two-photon imaging, flow cytometry, Western blot, immunohistochemistry, and quantitative polymerase chain reaction assay (qPCR). IFITM3 expression was increased in the CVECs of patients with AD. Overexpression of IFITM3 in primary endothelial cells enhanced Aβ generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ further increased IFITM3 expression, creating a vicious cycle. Knockdown of IFITM3 in CVECs decreased Aβ accumulation within cerebrovascular walls, reduced Alzheimer's-related pathology, and improved cognitive performance in AD transgenic mice. Knockdown of IFITM3 in CVECs alleviates AD pathology and cognitive impairment. Targeting cerebrovascular endothelial IFITM3 holds promise for AD treatment. Interferon-induced transmembrane protein 3 (IFITM3) expression was increased in the cerebrovascular endothelial cells (CVECs) of patients with Alzheimer's Disease (AD). Cerebrovascular endothelial IFITM3 regulates amyloid β protein (Aβ) generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Knockdown of IFITM3 in CVECs reduces Aβ deposits and improves cognitive impairments in AD transgenic mice. Cerebrovascular endothelial IFITM3 could be a potential target for the treatment of AD.

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.

BACE1 inhibitory potential: screening of medicinal plants collected from Nepal high altitude regions

Fifty-four plant extracts from thirty-two medicinal plants collected in Nepal were evaluated for their inhibitory potential against the enzyme beta-secretase-1 (BACE1), to identify potential therapeutic agents for Alzheimer’s disease (AD). Of the studied extracts, rhizome extract of Rheum australe D. Don showed the highest inhibitory potential, with an IC50 value of 0.872 ± 0.006 µg/mL. After BACE1 inhibitory activity check using 9 fractions collected from Prep-HPLC, further profiling of the metabolites of the best fraction 7 was performed using high-resolution mass spectrometry (HRMS). Results revealed the presence of diverse secondary metabolites, including aloe-emodin-8-O-β-D-glucoside, rhein-8-O-glucoside, piceatannol-3’-O-β-D-glucoside, emodin-8-glucoside, physcion 8-O-β-D-glucoside, desoxyrhaponticin, chrysophanol-8-O-glucoside, rhapontigenin, rhein, desoxyrhapontigenin, piceatannol, chrysophanol, physcion, and aloe-emodin. In-silico docking simulations were performed to identify potent compounds with high binding efficiencies to BACE1. Compound picetannol-3’-O-β-D-glucoside showed the best binding energy (-53.494 kcal/mol) and inhibitory potential with an IC50 value of 1.270 ± 0.130 µM for BACE1. These results suggested that the R. australe D. Don extract is a promising agent for the treatment of AD.

Genetic polymorphism in β-site amyloid precursor protein-cleaving enzyme1 affects the structure of medial temporal lobe and cognition in Alzheimer's disease: an exploratory study.

The β-site amyloid precursor protein-cleaving enzyme1 (BACE1) gene polymorphism (rs638405) has been widely reported to be associated with Alzheimer's disease (AD) risk. However, studies on the relationship between BACE1 gene polymorphism (rs638405), brain volume, and cognition in AD patients remain scarce. To investigate the effect of genetic polymorphism in BACE1 on gray matter volume (GMV) and cognition in AD, this study recruited 111 cognitively unimpaired (CU) controls and 144 AD patients. The effect of BACE1 rs638405 polymorphism on cognition was explored in CU and AD groups. Then the interaction effect of the diagnosis and BACE1 rs638405 polymorphism on GMV was performed, following the post-hoc analysis of regions of interest (ROIs) in interaction analysis. Mediation analysis was used to elucidate the relationship among genotypes, ROIs and cognition. BACE1 rs638405 G carriers (BACE1 G+) showed significantly lower scores in global cognition and memory function than noncarriers (BACE1 G-) in AD group. Genotypes (G+/G-) and diagnosis (CU/AD) have interaction on GMV of medial temporal lobe (MTL) including the left parahippocampus and right hippocampus. Post-hoc analysis revealed that BACE1 G+ exhibited significantly lower GMV in ROIs compared to BACE1 G- in AD. Finally, mediation analysis further demonstrated that the GMV of ROIs mediated the effect of BACE1 rs638405 polymorphism on cognition in AD. Our results emphasize the BACE1 rs638405 gene polymorphisms may affect the GMV of MTL and cognition in AD, deepening the understanding of AD pathogenesis.

Exploring the Therapeutic Potential of 8-Prenyldaidzein: A Comprehensive Study of its Multi-Target Efficacy in Alzheimer's Disease.

Alzheimer's disease (AD) is marked by cognitive decline, amyloid plaques, neurofibrillary tangles, and cholinergic loss. Due to the limited success of amyloid-targeted therapies, attention has shifted to new non-amyloid targets like phosphodiesterases (PDE). This study investigates the potential of Flemingia vestita (FV) phytomolecules and derivatives, particularly 8-Prenyldaidzein, in AD treatment. Phytocompounds and derivatives were screened for drug-likeness, toxicity, BBB permeability, and ADME profiles. Molecular docking was conducted with PDE5A, BACE-1, and AChE, followed by molecular dynamics (MD) simulations on the best binding complexes. 8-Prenyldaidzein, a derivative of daidzein, demonstrated favorable drug-likeness and ADME properties. It exhibited strong binding to PDE5A, BACE-1, and AChE, with MD simulations confirming stable protein-ligand interactions. The multi-target potential of 8-Prenyldaidzein, particularly through non-amyloid pathways, offers a promising approach to AD therapy. Its inhibition of PDE5A, BACE-1, and AChE could address multiple aspects of AD pathology. 8-Prenyldaidzein shows strong potential as a multi-target inhibitor for AD treatment. While in-silico findings are promising, further experimental validation is needed to confirm its clinical applicability.

Enhanced prediction of beta-secretase inhibitory compounds with mol2vec technique and machine learning algorithms

ABSTRACT A comprehensive computational strategy that combined QSAR modelling, molecular docking, and ADMET analysis was used to discover potential inhibitors for β-secretase 1 (BACE-1). A dataset of 1,138 compounds with established BACE-1 inhibitory activities was used to build a QSAR model using mol2vec descriptors and support vector regression. The obtained model demonstrated strong predictive performance (training set: r 2 = 0.790, RMSE = 0.540, MAE = 0.362; test set: r 2 = 0.705, RMSE = 0.641, MAE = 0.495), indicating its reliability in identifying potent BACE-1 inhibitors. By applying this QSAR model together with molecular docking, seven compounds (ZINC8790287, ZINC20464117, ZINC8878274, ZINC96116481, ZINC217682404, ZINC217786309 and ZINC96113994) were identified as promising candidates, exhibiting predicted log IC50 values ranging from 0.361 to 1.993 and binding energies ranging from −10.8 to −10.7 kcal/mol. Further analysis using ADMET studies and molecular dynamics simulations provided further support for the potential of compound 279 (ZINC96116481) and compound 945 (ZINC96113994) as drug candidates. However, since our study is purely theoretical, further experimental validation through in vitro and in vivo studies is essential to confirm these promising findings.

Magnesium-Phenolic Nanoeditor Refining Gliomatous T Cells for Metalloimmunotherapy.

More than the sparse infiltration in glioblastoma, cytotoxic T lymphocytes (CTLs) also function inefficiently and overexpress the inhibitory markers, especially the identified NK cell receptor (NK1.1). However, most studies solely focus on how to augment tumor-infiltrating CTLs and overlook their killing maintenance. Metalloimmunotherapy has been proven to improve the functionalities of CTLs, but it has barely adapted to glioblastoma due to the severe limitations of safe delivery and the brain's physiological properties. Herein, we synthesized an amphipathic polyethylene glycol (PEG) polymer (designated as MPP) modified with the choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) and polyphenol moieties to customize a nanoeditor (Mg2+@MK-8931@MPP) by coordinating Mg2+ and entrapping the hydrophobic BACE1 inhibitor MK-8931, then precisely redressing the gliomatous CTL sparsity and cytotoxic dysfunction. Upon MPC-assisted local accumulation in glioblastoma, Mg2+@MK-8931@MPP nanoeditors release MK-8931 to repolarize M2-like macrophages, facilitating CTL infiltration quantitatively. The cenogenetic immune adjuvant Mg2+ ulteriorly fortifies the T-cell receptor downstream signals to enhance the functionality of the ingoing CTLs in quality, leading to the secretion of high-level antitumor cytokines and cytotoxic proteins. Further blocking the inhibitory NK1.1 on CTLs by anti-NK1.1 antibodies can extend their cytolytic endgame. Studies on T-cell-deficient and wild-type mouse models support the immunomodulating feasibility of Mg2+@MK-8931@MPP. This gliomatous CTL-tailored strategy concurrently broadens metalloimmunotherapy to glioblastoma treatment and highlights the necessity of enforcing gliomatous CTLs' functionality.

Inhibitory Effects of Gliadin Hydrolysates on BACE1 Expression and APP Processing to Prevent Aβ Aggregation.

Alzheimer's disease (AD), a leading neurodegenerative disorder, is closely associated with the accumulation of amyloid-beta (Aβ) peptides in the brain. The enzyme β-secretase (BACE1), pivotal in Aβ production, represents a promising therapeutic target for AD. While bioactive peptides derived from food protein hydrolysates have neuroprotective properties, their inhibitory effects on BACE1 remain largely unexplored. In this study, we evaluated the inhibitory potential of protein hydrolysates from gliadin, whey, and casein proteins prepared using bromelain, papain, and thermolysin. Through in vitro and cellular assays, bromelain-hydrolyzed gliadin (G-Bro) emerged as the most potent BACE1 inhibitor, with an IC50 of 0.408 mg/mL. G-Bro significantly reduced BACE1 expression and amyloid precursor protein (APP) processing in N2a/PS/APP cell cultures, suggesting its potential to attenuate Aβ aggregation. The unique peptide profile of G-Bro likely contributes to its inhibitory effect, with proline residues disrupting β-sheets, lysine residues introducing positive charges that hinder aggregation, hydrophobic residues stabilizing binding interactions, and glutamine residues enhancing solubility and stability. These findings highlight gliadin hydrolysates, particularly G-Bro, as potential natural BACE1 inhibitors with applications in dietary interventions for AD prevention. However, further studies are warranted to elucidate specific peptide interactions and their bioactivity in neural pathways to better understand their therapeutic potential.

Structure-Based Virtual Screening and Biological Characterization of Novel BACE-1 and Amyloid-β Aggregation Inhibitors.

Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE-1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35 % inhibitory activity at 10 μM. Notably, pyrazole-5-carbohydrazide 29 (5784196) exhibited BACE-1 inhibition with an IC50 value of 14.5 μM and a ki value of 0.25 μM. Additionally, it also inhibits the self-aggregation of β-amyloid, with IC50 value of 14.87 μM. Molecular modeling and dynamics simulations provided insights into its interaction pattern and stability of the enzyme-inhibitor complex. These findings suggest that virtual screening is an efficient and cost-effective method for identifying potential leads for AD.

Neuroprotective Potential of Aminonaphthoquinone Derivatives Against Amyloid Beta-Induced Neuronal Cell Death Through Modulation of SIRT1 and BACE1

Alzheimer’s disease (AD) is characterized by the accumulation of tau protein tangles and amyloid-β (Aβ) plaques in the central nervous system (CNS), leading to progressive neurodegeneration. Hence, the discovery of disease-modifying agents capable of delaying the progression is essential for effective management. Aminonaphthoquinone (ANQ) is an attractive pharmacophore with various biological effects. This study explores the neuroprotective potentials of ANQ derivatives (1–18) using in vitro models of AD pathology (i.e., Aβ42-induced SH-SY5Y cells). Findings demonstrated that all compounds mitigated Aβ42-induced cellular damage by preserving cell viability and morphology. Among all, four compounds (10, 12, 16, and 18) showed potent antioxidant activities as well as abilities to minimize AD-related damages (i.e. decreasing intracellular reactive oxygen species (ROS) production, preserving mitochondrial membrane potential (MMP), protecting membrane damage, and modulating beta-secretase 1 (BACE1) activity) with comparable protective effects to the well-known neuroprotectant, resveratrol (RSV). A molecular docking study indicated these compounds could suitably bind to sirtuin 1 (SIRT1) protein with preferable affinity. Key amino acid residues and key functional groups essential for binding interactions were revealed. Target prediction identified a list of possible AD-related targets of these compounds offering insights into their mechanisms of action and suggesting their multifunctional potentials. Additionally, in silico predictions revealed that these candidates showed favorable drug-like properties. Overall, this study highlighted the therapeutic potential of ANQ derivatives in AD treatment, emphasizing the need for further experimental validation and comprehensive investigations to fully realize their therapeutic benefits.

Glyphosate exposure exacerbates neuroinflammation and Alzheimer’s disease-like pathology despite a 6-month recovery period in mice

BackgroundGlyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that C57BL/6J mice dosed with glyphosate for 14 days showed glyphosate and its major metabolite aminomethylphosphonic acid present in brain tissue, with corresponding increases in pro-inflammatory cytokine tumor necrosis factor-⍺ (TNF-⍺) in the brain and peripheral blood plasma. Since TNF-⍺ is elevated in neurodegenerative disorders such as Alzheimer’s Disease (AD), in this study, we asked whether glyphosate exposure serves as an accelerant of AD pathogenesis. Additionally, whether glyphosate and aminomethylphosphonic acid remain in the brain after a recovery period has yet to be examined.MethodsWe hypothesized that glyphosate exposure would induce neuroinflammation in control mice, while exacerbating neuroinflammation in AD mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. We dosed 4.5-month-old 3xTg-AD and non-transgenic (NonTg) control mice with either 0, 50 or 500 mg/kg of glyphosate daily for 13 weeks followed by a 6-month recovery period.ResultsWe found that aminomethylphosphonic acid was detectable in the brains of 3xTg-AD and NonTg glyphosate-dosed mice despite the 6-month recovery. Glyphosate-dosed 3xTg-AD mice showed reduced survival, increased thigmotaxia in the Morris water maze, significant increases in the beta secretase enzyme (BACE-1) of amyloidogenic processing, amyloid-β (Aβ) 42 insoluble fractions, Aβ 42 plaque load and plaque size, and phosphorylated tau (pTau) at epitopes Threonine 181, Serine 396, and AT8 (Serine 202, Threonine 205). Notably, we found increased pro- and anti-inflammatory cytokines and chemokines persisting in both 3xTg-AD and NonTg brain tissue and in 3xTg-AD peripheral blood plasma.ConclusionTaken together, our results are the first to demonstrate that despite an extended recovery period, exposure to glyphosate elicits long-lasting pathological consequences. As glyphosate use continues to rise, more research is needed to elucidate the impact of this herbicide and its metabolites on the human brain, and their potential to contribute to dysfunctions observed in neurodegenerative diseases.

Potential roles for BACE inhibitors in AD therapeutic trials

AbstractBackgroundNow, at the beginning of the era of disease‐modifying drugs for AD, many questions must be addressed in the effort to optimize benefits. Important issues remain regarding the timing and duration of amyloid‐removing immunotherapy and the potential advantages of combination therapies. Anti‐fibrillar amyloid antibodies effectively remove amyloid but may not be appropriate for maintenance of the low amyloid state; secretase inhibition is a reasonable alternative. Evidence suggests that the earlier amyloid is removed the larger the benefit; by extension, beginning anti‐amyloid therapy before plaque accumulation may be optimal but may require targeting the generation of amyloid monomers. The toxicity of diffusible amyloid species suggests that combining immunotherapy with secretase inhibition may provide additive benefit. As reviewed in this session, the availability of substantial pre‐clinical and clinical data on BACEi therapy suggests that this approach can provide fine‐tuned reduction in amyloid peptide generation while avoiding the reversible cognitive toxicity associated with this class of drug.MethodsFindings from trials with amyloid‐removing antibodies and various BACE inhibitors along with growing data on accurate plasma markers of AD neurobiology inform considerations of the next generation of trials needed to clarify the role of BACEi therapy for disease‐modification.ResultsExperience from ongoing clinical trials indicates that plasma biomarkers, particularly mass spectroscopy assays of abeta and ptau217 ratios, accurately predict amyloid levels by PET below the normal range. Further, changes in plasma ptau assays precede reaccumulation of fibrillar amyloid after cessation of amyloid‐lowering immunotherapy. These findings suggest that marrying accurate monitoring of plasma markers to BACEi therapy can provide a path to optimization of anti‐amyloid therapy. Future studies may demonstrate that screening individuals in late‐middle age with these plasma measures facilitates management of amyloid dysregulation at the pre‐plaque stage for primary prevention of AD.ConclusionCoupled with plasma biomarkers of AD pathology, BACE inhibitor therapy may provide a feasible approach to the optimization of anti‐amyloid therapy for established AD as well as primary prevention of the disease.