Neurodegenerative Research Articles

Cross-regulation of RNA methylation modifications and R-loops: from molecular mechanisms to clinical implications.

R-loops, RNA-DNA hybrid structures, are integral to key cellular processes such as transcriptional regulation, DNA replication, and repair. However, aberrant accumulation of R-loops can compromise genomic integrity, leading to the development of various diseases. Emerging evidence underscores the pivotal role of RNA methylation modifications, particularly N6-methyladenosine (m6A) and 5-methylcytosine (m5C), in orchestrating the formation, resolution, and stabilization of R-loops. These modifications dynamically regulate R-loop metabolism, exerting bidirectional control by either facilitating or resolving R-loop structures during gene expression regulation and DNA damage repair. Dysregulation of RNA methylation and the resultant imbalance in R-loop homeostasis are closely linked to the pathogenesis of diseases such as cancer and neurodegenerative disorders. Thus, deciphering the cross-talk between RNA methylation and R-loops is essential for understanding the mechanisms underlying genomic stability and identifying novel therapeutic targets. This review provides a comprehensive analysis of the role of RNA methylation in R-loop dynamics, examines their physiological and pathological implications, and proposes future directions for therapeutic intervention targeting these processes.

Association of Changes in Cerebral and Hypothalamic Structure With Sleep Dysfunction in Patients With Genetic Frontotemporal Dementia.

Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD). Hypothalamic nuclei important for sleep regulation may be related to this dysfunction. Thus, we examined changes in hypothalamic structure across the lifespan in patients with genetic FTD and whether these changes related to sleep dysfunction. Data from the observational multisite Genetic Frontotemporal Dementia Initiative (GENFI) study were used. GENFI participants were adult members of a family with known pathogenic variants in the microtubule-associated protein tau (MAPT) or progranulin (GRN) genes or an expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Family members without a pathogenic variant served as controls. GENFI participants were followed annually, with up to 7 visits, and underwent clinical characterization, neuropsychological testing, biological sampling, and brain MRI. For our analyses, participants were included if they had at least 1 T1-weighted structural MRI scan available. Linear mixed-effect models were used to examine changes in sleep dysfunction, measured using the Cambridge Behavioural Inventory-Revised sleep subscale, volumetric changes in hypothalamic regions, and the associations between cortical and hypothalamic atrophy and sleep dysfunction. Participants included 491 adults with pathogenic genetic variants of FTD (27.9% symptomatic; median age: 49.4 years, 56.4%F) and 321 controls (median age: 44.2 years, 57.3%F). Pathogenic variant carriers showed greater sleep dysfunction across the adult lifespan (β = [0.25-0.34], q < 0.005) with MAPT carriers alone showing presymptomatic sleep changes (β = 0.34, q = 0.005). Cortical thinning in frontal and parietal regions was associated with greater sleep disturbances in C9orf72 and GRN carriers (q < 0.05). MAPT carriers showed consistently significant volume loss over time across all sleep-relevant hypothalamic subunits (β = [-0.56 to -0.39], q < 0.005), and reduced volumes in these subunits were related to increased sleep dysfunction (β = [-0.20 to -0.16], q < 0.05). These findings suggest that sleep dysfunction in patients with genetic FTD may be attributable to atrophy in sleep-relevant hypothalamic subunits, with the most severe and consistent deficits observed in MAPT carriers. While biologically plausible, our statistical approach cannot confirm a causal link between atrophy and sleep disturbances.

Advanced Glycation End Products in Neurodegenerative Diseases.

Advanced glycation end products (AGEs) have attracted interest as therapeutic targets for neurodegenerative diseases. AGEs facilitate the onset and progression of various neurogenerative disorders due to their ability to promote cross-linking and aggregation of proteins. Further, the interaction between AGEs and receptor for AGEs (RAGE) activates neuroinflammatory, oxidative stress and excitotoxicity processes that contribute to neuronal cell death. Various therapeutic efforts have targeted lowering the production of AGEs, inhibiting RAGE or inhibiting some of the processes of the AGE-RAGE axis as potential treatments for these disorders. Whereas effective treatments for many neurodegenerative disorders remain elusive, such efforts offer promise to slow the progression of diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD).

Bacopaside-I ameliorates motor dysfunction and neurodegeneration in rat model of Parkinson's disease.

Chronic administration of Bacopa monnieri extract exerts neuroprotective potential in multiple animal models of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), depression, and other cognitive impairments. However, the underlying mechanism of action remained unclear. Rotenone model of PD holds a great potential for investigating PD pathology and motor and nonmotor symptoms. Herein, we evaluated the neuroprotective effect of Bacopaside-I (BS-I), a major triterpenoid saponin of Bacopa monnieri extract, against rotenone-induced in vivo model of PD and explored the possible molecular mechanism. Rats were exposed to rotenone (2mg/kg body weight) for a period of 4 consecutive weeks to induce PD-like behavior. BS-I (5, 15, and 45mg/kg) was administered orally. Behavioral data (rotarod, foot printing, and grip strength test) suggest that BS-I plays a significant role in attenuating the motor function deficit. Exposure to rotenone reduces the dopamine level and increases oxidative stress, while BS-I treatment reversed these changes. Furthermore, chronic administration of BS-I increased the expression levels of dopamine transporter (DAT) and vesicular monoamine transporter (VMAT) genes and the numbers of tyrosine hydroxylase (TH)-positive neurons as compared to rotenone-exposed animals. Our study established the neuroprotective role of BS-I in PD model and laid the foundation for further evaluation of BS-I-based drug in future studies.

Exploring the molecular mechanisms of curcumin in modulating memory impairment in neurodegenerative disorders.

Memory impairment is a critical challenge in neurodegenerative disorders, particularly in Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. This research explores the molecular mechanisms by which curcumin, a polyphenolic compound derived from Curcuma longa, exerts neuroprotective effects that may ameliorate cognitive deficits associated with these conditions. Evidence from both preclinical studies and emerging clinical trials indicates that curcumin enhances neuronal signaling and synaptic plasticity, primarily through the modulation of pathways such as NF-κB and PI3K/Akt. Specifically, curcumin has been shown to reduce neuroinflammation and oxidative stress, thereby promoting synaptic integrity and function. For instance, studies demonstrate that curcumin treatment increases the density of dendritic spines in the hippocampus, which correlates with improved spatial learning and memory performance in animal models. Despite promising findings, significant gaps remain in our understanding of curcumin's efficacy in humans. Most existing research is derived from animal studies, with limited large-scale clinical trials to substantiate its therapeutic potential. Furthermore, challenges such as curcumin's low bioavailability and inconsistencies in dosing complicate its clinical application. This review underscores the need for future research focused on enhancing curcumin's bioavailability, establishing optimal dosages, and conducting comprehensive human trials to validate its effectiveness. By addressing these issues, we aim to clarify curcumin's role as a potential therapeutic agent for memory impairment in neurodegenerative disorders, paving the way for innovative treatment strategies.

Efficacy of red algae and artichoke extracts in disrupting antioxidant/PI3K/RBP-4 pathway in high-fat diet-induced metabolic disorders in rats

BackgroundInsulin resistance (IR) leads to various metabolic abnormalities, including diabetes mellitus, obesity, nonalcoholic steatohepatitis, and neurodegenerative disorders. Natural products rich in nontoxic phytochemicals are cost-effective and widely used to manage insulin resistance, reducing drug interactions. Artichoke stems and red algae contain several phytochemical compounds that exert antioxidant and anti-inflammatory effects.AimThis study aims to explore and compare the preventive and therapeutic effects of red algae and artichoke stem extracts against high-fat diet-induced insulin resistance and then compare their impacts with those of the reference drug metformin, which is commonly used for treating type 2 diabetes.MethodsThe animals were fed a high-fat diet for eight weeks to induce insulin resistance. The plants were then treated orally with 100 mg/kg body weight red algae, artichoke extracts, or metformin per day for 14 days. The protective rat groups received the extracts at the same dose for 14 days before being fed the high-fat diet for eight weeks. Commercial kits and standardized methods were used to measure blood diabetic profiles (glucose, insulin, lipid profile, fructosamine, and retinol-binding protein-4 (RBP-4)) and liver oxidative stress parameters, nuclear factor-κβ (NF-κβ), peroxisome proliferator-activated receptor gamma (PPAR-γ), phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), retinol-binding protein-4 (RBP-4), and phosphatase and tensin homolog (PTEN).ResultsOur results showed that both extracts inhibited NF-κB and PTEN while enhancing PI3K, RPB-4, and PPAR-γ due to their potent antioxidant properties. They also increased insulin sensitivity, as reflected by reduced blood glucose and lipid profile levels and normalized fructosamine and RBP-4. Additionally, these extracts prevent oxidative stress-induced hepatic and nephric cell dysfunction, as confirmed by improved blood, liver, and kidney parameters.ConclusionTherefore, both extracts could be good antioxidant treatments for oxidative stress-related insulin resistance because they restore the balance of the PI3K/PPAR-γ/RBP-4 pathway. This pathway increases glucose uptake, stops gluconeogenesis, speeds up lipid metabolism, and stops the inflammation pathway.

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type-specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types and validated in independent snRNA-seq and bulk RNA-seq datasets. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.

Discovery of a Small Molecule with an Inhibitory Role for RAB11

RAB11, a pivotal RabGTPase, regulates essential cellular processes such as endocytic recycling, exocytosis, and autophagy. The protein was implicated in various human diseases, including cancer, neurodegenerative disorders, viral infections, and podocytopathies. However, a small-molecular inhibitor is lacking. The complexity and workload associated with potential assays make conducting large-scale screening for RAB11 challenging. We employed a tiered approach for drug discovery, utilizing deep learning-based computational screening to preselect compounds targeting a specific pocket of RAB11 protein with experimental validation by an in vitro platform reflecting RAB11 activity through the exocytosis of GFP. Further validation included the exposure of Drosophila by drug feeding. In silico pre-screening identified 94 candidates, of which 9 were confirmed using our in vitro platform for Rab11 activity. Focusing on compounds with high potency, we assessed autophagy, which independently requires RAB11, and validated three of these compounds. We further analyzed the dose–response relationship, observing a biphasic, potentially hormetic effect. Two candidate compounds specifically caused a shift in Rab11 vesicles to the cell periphery, without significant impact on Rab5 or Rab7. Drosophila larvae exposed to another candidate compound with predicted oral bioavailability exhibited minimal toxicity, subcellular dispersal of endogenous Rab11, and a decrease in RAB11-dependent nephrocyte function, further supporting an inhibitory role. Taken together, the combination of computational screening and experimental validation allowed the identification of small molecules that modify the function of Rab11. This discovery may further open avenues for treating RAB11-associated disorders.

Trusted explainable AI based implementation for detection of neurodegenerative disorders (ND)

Trusted explainable AI based implementation for detection of neurodegenerative disorders (ND)

Machine learning based algorithms for virtual early detection and screening of neurodegenerative and neurocognitive disorders: a systematic-review

Background and aimNeurodegenerative disorders (e.g., Alzheimer’s, Parkinson’s) lead to neuronal loss; neurocognitive disorders (e.g., delirium, dementia) show cognitive decline. Early detection is crucial for effective management. Machine learning aids in more precise disease identification, potentially transforming healthcare. This comprehensive systematic review discusses how machine learning (ML), can enhance early detection of these disorders, surpassing traditional diagnostics’ constraints.MethodsIn this review, databases were examined up to August 15th, 2023, for ML data on neurodegenerative and neurocognitive diseases using PubMed, Scopus, Google Scholar, and Web of Science. Two investigators used the RAYYAN intelligence tool for systematic reviews to conduct the screening. Six blinded reviewers reviewed titles/abstracts. Cochrane risk of bias tool was used for quality assessment.ResultsOur search found 7,069 research studies, of which 1,365 items were duplicates and thus removed. Four thousand three hundred and thirty four studies were screened, and 108 articles met the criteria for inclusion after preprocessing. Twelve ML algorithms were observed for dementia, showing promise in early detection. Eighteen ML algorithms were identified for Parkinson’s, each effective in detection and diagnosis. Studies emphasized that ML algorithms are necessary for Alzheimer’s to be successful. Fourteen ML algorithms were discovered for mild cognitive impairment, with LASSO logistic regression being the only one with unpromising results.ConclusionThis review emphasizes the pressing necessity of integrating verified digital health resources into conventional medical practice. This integration may signify a new era in the early detection of neurodegenerative and neurocognitive illnesses, potentially changing the course of these conditions for millions globally. This study showcases specific and statistically significant findings to illustrate the progress in the area and the prospective influence of these advancements on the global management of neurocognitive and neurodegenerative illnesses.

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.

Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes.

Friedreich's ataxia (FRDA) is a neurodegenerative disorder characterized by severe neurological signs, affecting the peripheral and central nervous system, caused by reduced frataxin protein (FXN) levels. While several studies highlight cellular dysfunctions in neurons, there is limited information on the effects of FXN depletion in astrocytes and on the potential non-cell autonomous mechanisms affecting neurons in FRDA. In this study, we generated a model of FRDA cerebellar astrocytes to unveil phenotypic alterations that might contribute to cerebellar atrophy. We treated primary cerebellar astrocytes with an RNA interference-based approach, to achieve a reduction of FXN comparable to that observed in patients. These FRDA-like astrocytes display some typical features of the disease, such as an increase of oxidative stress and a depletion of glutathione content. Moreover, FRDA-like astrocytes exhibit decreased calcium responses to purinergic stimuli. Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, likely impairing their complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators in a calcium-dependent manner could affect neuronal function, contributing to neurodegeneration.

Exploration of Novel Biomarkers for Neurodegenerative Diseases Using Proteomic Analysis and Ligand-Binding Assays

Background/Objectives: Neurodegenerative diseases are a major cause of morbidity and mortality worldwide, and their public health burden continues to increase. There is an urgent need to develop reliable and sensitive biomarkers to aid the timely diagnosis, disease progression monitoring, and therapeutic development for neurodegenerative disorders. Proteomic screening strategies, including antibody microarrays, are a powerful tool for biomarker discovery, but their findings should be confirmed using quantitative assays. The current study explored the feasibility of combining an exploratory proteomic strategy and confirmatory ligand-binding assays to screen for and validate biomarker candidates for neurodegenerative disorders. Methods: It analyzed cerebrospinal fluid (CSF) and plasma samples from patients with Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis and healthy controls using an exploratory antibody microarray and validatory ligand-binding assays. Results: The screening antibody microarray identified differentially expressed proteins between patients with neurodegenerative diseases and healthy controls, including cluster of differentiation 14 (CD14), osteopontin, and vascular endothelial growth factor 165b. Quantitative ligand-binding assays confirmed that CD14 levels were elevated in CSF of patients with Alzheimer’s disease (p = 0.0177), whereas osteopontin levels were increased in CSF of patients with Parkinson’s disease (p = 0.0346). Conclusions: The current study demonstrated the potential utility of combining an exploratory proteomic approach and quantitative ligand-binding assays to identify biomarker candidates for neurodegenerative disorders. To further validate and expand these findings, large-scale analyses using well-characterized samples should be conducted.

Transmission of Peripheral-blood α-Synuclein Fibrils Exacerbates Synucleinopathy and Neurodegeneration in Parkinson's Disease by Endothelial Lag3 Endocytosis.

Background: Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal alpha-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFF) can be detected in the serum of PD patients. The peripheral-blood α-syn PFF can cross the blood-brain barrier and aggravate neuronal damage, but the mechanism remains to be elucidated. Methods: We constructed the PD mouse models of different severity: the mild pathology (A53T ONLY) and the severe pathology (A53T+Brain FIB); this was followed by α-syn PFFs intravenous injection. Then, we used endothelium-specific Lag3 knockout mice (Lag3-ECs-CKO) to decrease the blood α-syn PFFs spreading. Results: We observed that intravenous transmission of α-syn PFFs significantly aggravated motor deficits, dopaminergic neuron loss, neuroinflammation and pathologic α-syn deposition in A53T ONLY, but not in A53T+Brain FIB. Blocking endothelial Lag3 endocytosis by Lag3-ECs-CKO decreased the blood α-syn PFFs spreading and improved the symptoms and pathogenesis of PD mice. Conclusions: Our findings reveal the role of peripheral-blood α-syn PFFs transmission in the mild pathology or early-stage PD and the mechanism of endothelial Lag3 endocytosis in the pathology of α-syn transmission. Targeting endothelial Lag3 to prevent α-syn from spreading from the blood to the brain may be a disease-modifying therapy in early-stage PD.

Emerging Biomarkers in Metabolomics: Advancements in Precision Health and Disease Diagnosis

Metabolomics has come to the fore as an efficient tool in the search for biomarkers that are critical for precision health approaches and improved diagnostics. This review will outline recent advances in biomarker discovery based on metabolomics, focusing on metabolomics biomarkers reported in cancer, neurodegenerative disorders, cardiovascular diseases, and metabolic health. In cancer, metabolomics provides evidence for unique oncometabolites that are important for early disease detection and monitoring of treatment responses. Metabolite profiling for conditions such as neurodegenerative and mental health disorders can offer early diagnosis and mechanisms into the disease especially in Alzheimer’s and Parkinson’s diseases. In addition to these, lipid biomarkers and other metabolites relating to cardiovascular and metabolic disorders are promising for patient stratification and personalized treatment. The gut microbiome and environmental exposure also feature among the influential factors in biomarker discovery because they sculpt individual metabolic profiles, impacting overall health. Further, we discuss technological advances in metabolomics, current clinical applications, and the challenges faced by metabolomics biomarker validation toward precision medicine. Finally, this review discusses future opportunities regarding the integration of metabolomics into routine healthcare to enable preventive and personalized approaches.

Psychiatric Disorders and Cognitive Fluctuations in Parkinson’s Disease: Changing Approaches in the First Decades of the 21st Century

Parkinson’s Disease (PD) is a multifaceted neurodegenerative disorder characterized, in addition to the well-recognized motor disturbances, by a complex interplay between cognitive and psychiatric manifestations. We dissect the complex landscape of PD-related psychiatric symptoms, taking into account the impact of functional neurological disorders, somatic delusions, impulse control disorders, and conditions within the bipolar spectrum. The newer entities of somatoform and functional neurological disorders, as well as preexisting bipolar spectrum disorders, are analyzed in detail. Moreover, we emphasize the need for a holistic understanding of PD, wherein the cognitive and psychiatric dimensions are valued alongside motor symptoms. Such an approach aims to facilitate early detection and personalized interventions, and enhance the overall quality of life for individuals suffering from this neurodegenerative disorder.

Gross motor delays in infants and young boys with Duchenne muscular dystrophy

Background Duchenne muscular dystrophy (DMD), an X-linked progressive neurodegenerative disorder, is being added to required universal screening programs for newborns in the United States. It is estimated that this will result in around 880 patients presenting at clinics in infancy. Very little is known about the early gross motor abilities in infants and young boys with DMD. Objective Describe the early gross motor skill acquisition in boys in our clinic with DMD. Methods Between the years 2016 and 2024, 90 boys with DMD under the age of 6 years (2 months – 5 years 10 months at their first visit) were evaluated as part of their standard of care during regularly scheduled clinic visits using the using the Bayley Scales of Infant &amp; Toddler Development, Third Edition (Bayley-III). Forty-seven boys were seen in clinic longitudinally with two to six follow up visits for a total of 129 assessments. Results Ninety four percent of the boys with DMD seen in our clinic demonstrated delays in gross motor skills across the age span when compared with normative controls. None of the boys reached a ceiling on the Bayley-III despite being older than the intended age range of the test. Conclusions Our clinic data showed an almost universal gross motor delay in infants and toddlers that did not diminish over time.

The effectiveness of music therapy for the treatment of Alzheimer's disease

Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most prevalent cause of dementia. It is caused by the degeneration of brain cells due to the accumulation of intracellular hyperphosphorylated tau - containing neurofibrillary tangles and extracellular plaques of amyloid-beta peptide. While pharmacotherapy remains the main form of treatment (including cholinesterase inhibitors and antagonists to NMDA), various non-pharmacological therapy modalities have gained increasing attention as complementary treatment options, such as music therapy. Purpose of the study: This review examines the role of music therapy as an important complement to baseline therapy for AD patients, focusing on indications, methods, and the prospect of music therapy. Materials and methods: A comprehensive literature review was conducted, analyzing 48 studies from the PubMed database (English-language, up to November 2024) that assess the efficacy, methods, and prospect of music therapy as an adjunctive therapy in Alzheimer’s disease. Conclusions: Music therapy is an established and effective supportive treatment for AD patients. It has demonstrated clinical success over many years as a tool for engaging multiple motor and sensory areas, shaping emotions, and evoking memories. This may be due to activating limbic and paralimbic structures, enhancing neuroplasticity, and modulating neurotransmitter systems. Despite the observable benefits of music therapy, the methodological limitations of existing studies highlight the need for further long-term research to standardize treatment approaches.

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.

Inhibition of Bone Morphogenetic Protein Signaling Prevents Tau Pathology in iPSC Derived Neurons and PS19 Mice.

Many neurodegenerative disorders share a common pathologic feature involving the deposition of abnormal tau protein in the brain (tauopathies). This suggests that there may be some shared pathophysiologic mechanism(s). The largest risk factor for the majority of these disorders is aging, suggesting involvement of the aging process in the shared pathophysiology. We test the hypothesis that an increase in bone morphogenetic protein (BMP) signaling that occurs during aging contributes to the onset and progression of tauopathies. Human induced pluripotent stem cell (iPSC)-derived neurons from patients with Alzheimer's disease (AD) were used to investigate the effects of BMP signaling on tau phosphorylation and release and the mechanisms underlying these effects. Wildtype mice were used to examine effects of BMP signaling in vivo. P301S (PS19) mice were examined for the effects of BMP signaling in a model of tauopathy. Here, we show that BMP signaling, mediated by non-canonical p38 signaling, increases tau phosphorylation and release of p-tau in human iPSC-derived AD neurons. Further, there is an interaction between BMP signaling and apolipoprotein E4 (ApoE4) that significantly increases tau phosphorylation and release compared with ApoE3 neurons. Inhibiting BMP signaling reduces the changes in tau in the cultured human neurons, and it limits tau pathology and prevents cognitive decline in PS19 mice. Our study suggests that the age-related increase in BMP signaling may participate in the onset and progression of tau pathology. Thus, therapeutic interventions that reduce BMP signaling in the aging brain could potentially slow or prevent development of diseases involving tau hyperphosphorylation. ANN NEUROL 2024.