Senile Plaques Research Articles

Zebrafish Experimental Animal Models for AD: A Comprehensive Review.

AD disease (AD) is a multifaceted and intricate neurodegenerative disorder characterized by intracellular neurofibrillary tangle (NFT) formation and the excessive production and deposition of Aβ senile plaques. While transgenic AD models have been found instrumental in unravelling AD pathogenesis, they involve cost and time constraints during the preclinical phase. Zebrafish, owing to their simplicity, well-defined behavioural patterns, and relevance to neurodegenerative research, have emerged as a promising complementary model. Zebrafish possess glutaminergic and cholinergic pathways implicated in learning and memory, actively contributing to our understanding of neural transmission processes. This review sheds light on the molecular mechanisms by which various neurotoxic agents, including okadaic acid (OKA), cigarette smoke extract, metals, and transgenic zebrafish models with genetic similarities to AD patients, induce cognitive impairments and neuronal degeneration in mammalian systems. These insights may facilitate the identification of effective neurotoxic agents for replicating AD pathogenesis in the zebrafish brain. In this comprehensive review, the pivotal role of zebrafish models in advancing our comprehension of AD is emphasized. These models hold immense potential for shaping future research directions and clinical interventions, ultimately contributing to the development of novel AD therapies.

Review on Alzheimers Disease

Abstract: Loss of Abstract Thinking Someone with Alzheimer’s disease may lose the ability to draw conclusions and solve problems. It may become difficult to balance a checkbook, for example, because the patient has forgotten what to do with the numbers. About 29.8 million people worldwide had been diagnosed with Alzheimer’s disease (AD) in 2015, And the number is projected to triple by 2050. In 2018, AD was the fifth leading cause of death in Americans with 65 years of age or older, but the progress of AD drug research is very limited. It is Helpful to identify the key factors and research trends of AD for guiding further more effective Studies. Alzheimer’s disease is a degenerative disease of the brain, the most common cause of dementia in the geriatric population, and a major cause of death. Alzheimer’s disease is one of the fastest growing risk factors in middle age, which Increases the risk of Alzheimer’s disease in coronary weddings and higher levels of Homocysteine, which can lead to withdrawal due to lifestyle changes. Cigarettes prevent Alzheimer’s disease by recalling memories. Also, despite the fact that there is no Definitive cure for Alzheimer’s, the ability to increase acetylcholine levels and reduce Ameloid beta deposition and your medications such as Donepezil has proven to be very Effective when treating Alzheimer’s disease (AD) is a progressive neurodegenerative disease. It Is characterized by progressive cognitive deterioration together with Declining activities of daily living and behavioral changes. It is the Most common type of pre-senile and senile dementia. Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence Extracellular b-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphos . Phorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles For other critical cellular and molecular processes. Despite this, no disease-modifying treatment Currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here ,We review recent advances in our understanding of AD pathobiology and discuss current treatment Strategies, highlighting recent clinical trials and opportunities for developing future disease modifying therapies.

Blockade of brain alkaline phosphatase efficiently reduces amyloid-β plaque burden and associated cognitive impairment

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease. Three new drugs for AD based on monoclonal antibodies against the amyloid-β peptide (Aβ) have recently been approved because they favor the reduction of the burden of senile plaque in the AD patient’s brain. Nonetheless, both drugs have very limited applicability and benefits and show several side effects. These limitations invite us to find alternative strategies for treating patients with AD. Here, we explored whether tissue-nonspecific alkaline phosphatase (TNAP), an ectoenzyme upregulated in the brain of AD patients and whose inhibition has beneficial effects on tau-induced pathology, is also efficient in reducing senile plaque burden.MethodsTo evaluate whether TNAP may reduce cerebral senile plaque loading and Aβ-related toxicity, we use both pharmacological and genetic approaches. We analyze postmortem samples from human AD patients, APP/PS1 mice (a mouse model that mimics amyloid pathology observed in AD patients) treated or not with TNAP inhibitors, and the newly generated transgenic mouse line, TNAP-deficient APP/PS1 mice.ResultsFor the first time, we describe that genetic or pharmacological blockade of TNAP effectively reduces senile plaque burden by promoting its clearance, which leads to amelioration of cognitive impairment caused by Aβ-induced toxicity. These beneficial effects of TNAP inhibition occur concomitantly with higher microglial recruitment toward the senile plaque and increased microglial phagocytic capacity of Aβ by a mechanism involving metalloprotease-depending osteopontin processing. In addition, we also found that TNAP blockade favors LRP1-mediated transport of Aβ through the BBB.ConclusionsHere, we have shown that TNAP inhibition effectively reduces brain senile plaque burden and associated behavioral defects. Furthermore, given that we had previously reported that TNAP blockade also ameliorates Tau-induced neurotoxicity and increases lifespan of P301S tauopathy mouse model, we can state that TNAP blockade may be a novel and efficient therapy for treating patients with AD.

Beta-Amyloid and Its Asp7 Isoform: Morphological and Aggregation Properties and Effects of Intracerebroventricular Administration.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of aggregated beta-amyloid (Aβ) protein in the form of senile plaques within brain tissue. Senile plaques contain various post-translational modifications of Aβ, including prevalent isomerization of Asp7 residue. The Asp7 isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis in brain tissue of transgenic mice. The toxicity of Aβ peptides may be partly mediated by their structure and morphology. In this respect, in this study we analyzed the structural and aggregation characteristics of the Asp7 isoform of Aβ42 and compared them to those of synthetic Aβ42. We also investigated the effects of intracerebroventricular (i.c.v.) administration of these peptides, a method often used to induce AD-like symptoms in rodent models. Atomic force microscopy (AFM) was conducted to compare the morphological and aggregation properties of Aβ42 and Asp7 iso-Aβ42. The effects of i.c.v. stereotaxic administration of the proteins were assessed via behavioral analysis and reactive oxygen species (ROS) estimation in vivo using a scanning ion-conductance microscope with a confocal module. AFM measurements revealed structural differences between the two peptides, most notably in their soluble toxic oligomeric forms. The i.c.v. administration of Asp7 iso-Aβ42 induced spatial memory deficits in rats and elevated oxidative stress levels in vivo, suggesting a potential of ROS in the pathogenic mechanism of the peptide. The findings support the further investigation of Asp7 iso-Aβ42 in translational research on AD and suggest its involvement in neurodegenerative processes.

Effect of diffusivity of amyloid beta monomers on the formation of senile plaques.

Alzheimer's disease (AD) presents a perplexing question: why does its development span decades, even though individual amyloid beta (Aβ) deposits (senile plaques) can form rapidly in as little as 24 hours, as recent publications suggest? This study investigated whether the formation of senile plaques can be limited by factors other than polymerization kinetics alone. Instead, their formation may be limited by the diffusion-driven supply of Aβ monomers, along with the rate at which the monomers are produced from amyloid precursor protein (APP) and the rate at which Aβ monomers undergo degradation. A mathematical model incorporating the nucleation and autocatalytic process (via the Finke-Watzky model), as well as Aβ monomer diffusion, was proposed. The obtained system of partial differential equations was solved numerically, and a simplified version was investigated analytically. The computational results predicted that it takes approximately 7 years for Aβ aggregates to reach a neurotoxic concentration of 50 μM. Additionally, a sensitivity analysis was performed to examine how the diffusivity of Aβ monomers and their production rate impact the concentration of Aβ aggregates.

Comparative Study of GPT-4Vision and Convolutional Neural Networks in Histopathological Image Analysis

Abstract Introduction/Objective Recent advancements in artificial intelligence (AI), particularly with Large Language Models like ChatGPT-4Vision (GPT-4V), have expanded the potential for automated interpretation of medical images. This study evaluates the diagnostic accuracy of GPT-4V in histopathological analysis of neurodegenerative diseases and compares its performance with traditional Convolutional Neural Networks (CNNs). Methods/Case Report We utilized 1515 histopathological images, including hematoxylin and eosin (H&E) staining and tau immunohistochemistry, from patients with various neurodegenerative diseases, such as Alzheimer’s disease, progressive supranuclear palsy, and corticobasal degeneration. GPT-4V’s performance was assessed through multi- step prompts to assess how textual context influences the image interpretation. In the quantitative analysis, the diagnostic accuracy of GPT-4V and the CNN-based model YOLOv8 was assessed for classifying three tau lesions—astrocytic plaques, neuritic plaques, and tufted astrocytes. The analysis used both zero-shot and few-shot learning methods, where GPT-4V and YOLOv8 were evaluated on their ability to distinguish these lesions using ten hold-out test images and 490 training images per lesion. Results (if a Case Study enter NA) GPT-4V accurately recognized Lewy bodies in all cases, but it showed limited accuracy in identifying neurofibrillary tangles (20%) and Pick bodies (0%) on H&E slides. Notably, GPT-4V often suggested Alzheimer’s disease as a potential diagnosis, relying more on contextual clues, such as the prevalence of certain diseases, rather than direct image analysis. In the tau immunohistochemical analysis, GPT-4V’s diagnoses were strongly influenced by additional information about staining and brain region. However, few-shot learning markedly improved GPT-4V’s diagnostic capabilities from 40% accuracy with zero-shot learning to 90% with few-shot learning, reaching best accuracy with 20-shot learning. This performance compared favorably against YOLOv8, which also achieved 90% accuracy but required 100-shot learning. Conclusion While GPT-4V faces challenges in independently interpreting histopathological images, few-shot learning significantly improves its accuracy. This approach is particularly promising for neuropathology, where acquiring extensive labeled datasets is challenging. The findings highlight the need for ongoing refinement of AI applications in pathology, emphasizing balanced integration of textual and visual data to optimize diagnostic efficacy and reliability.

Development and characterization of novel anti-acetylated tau monoclonal antibodies to probe pathogenic tau species in Alzheimer’s disease

Tauopathies, including Alzheimer’s disease (AD), are a class of neurodegenerative diseases characterized by the presence of insoluble tau inclusions. Tau phosphorylation has traditionally been viewed as the dominant post-translational modification (PTM) controlling tau function and pathogenesis in tauopathies. However, we and others have identified tau acetylation as a primary PTM regulating both normal tau function as well as abnormal pathogenic features including aggregation. Prior work showed robust tau acetylation in aggregation hotspots located within the 2nd and 3rd repeat regions of tau (residues K280 and K311) in tauopathy brains, including AD, compared to non-tauopathy controls. By screening thousands of hybridoma clones, we generated site-specific and modification-specific monoclonal antibodies targeting acetylated tau at residues K280 or K311. To validate these antibodies in a bona fide neuronal system, we targeted the acetyltransferase CBP to the cytoplasm of neurons to promote tau acetylation. Several antibody clones specifically detected CBP-acetylated tau and co-localized with ac-tau in neurons. Additionally, our lead optimal anti-acetylated-tau monoclonal antibodies detected robust tau pathology in tangles and neuritic plaques of human AD brains. Given the now emerging interest in acetylated tau as critical regulator of tau functions, these sensitive and highly specific tools will allow us to further unravel the tau PTM code and, importantly, could be deployed as diagnostic or disease-modifying agents.

Ferroptosis and pathogenesis of neuritic plaques in Alzheimer's Disease.

Neuritic plaques are pathognomonic and terminal lesions of Alzheimer's Disease (AD). They embody AD pathogenesis because they harbor in one space critical pathologic features of the disease: amyloid deposits, neurofibrillary degeneration (NFD), neuroinflammation, iron accumulation. Neuritic plaques are thought to arise from the conversion of diffuse extracellular deposits of amyloid beta protein (Aβ), and it is believed that during conversion amyloid toxicity creates the dystrophic neurites of neuritic plaques, as well as neurofibrillary tangles (NFTs). However, recent evidence from human post-mortem studies suggests a much different mechanism of neuritic plaque formation where the first step in their creation is neuronal degeneration driven by iron overload and ferroptosis. Similarly, NFTs represent corpses of iron-laden neurons that develop independent of Aβ deposits. In this review, we will focus on the role of free redox-active iron in the development of typical AD pathology, as determined largely by evidence obtained in human temporal lobe during early, preclinical stages of AD. The findings have allowed construction of a scheme of AD pathogenesis where brain iron is center stage and is involved in every step of the sequence of events that produce characteristic AD pathology. We will discuss how the study of preclinical AD has produced a fresh and revised assessment of AD pathogenesis that may be important for reconsidering current therapeutic efforts and guiding future ones. Significance Statement This review offers a novel perspective on AD pathogenesis where elevated brain iron plays a central role and is involved throughout the development of lesions. We review arguments against the amyloid cascade theory and explain how recent findings in humans during early preclinical disease support iron-mediated cell death and endogenous iron containment mechanisms as critical components of neuritic plaque formation and the ensuing dementia.

Ameliorative effects of aqueous extract of Colocasia esculenta leaf against lipopolysaccharide-induced prefrontal cortex damage in mice

IntroductionThe prefrontal cortex (PFC), crucial for cognition and memory, occupies a third of the cerebral cortex. This study investigated the protective effects of aqueous extract of Colocasia esculenta leaf (AECEL) against lipopolysaccharide (LPS)-induced PFC damage in mice.Methods42 male Swiss albino mice (18–22 g) were divided into six groups. Group A: healthy controls. Groups B-F received daily intraperitoneal LPS injections (0.5 mg/kg) for seven days. Group B: received distilled water, (2 ml) subsequently. Groups C-E: AECEL at 400, 600, and 800 mg/kg, respectively. Group F: donepezil (DPZ, 2.5 mg/kg) by oral gavage. All treatments continued for 28 days.ResultsLPS exposure significantly increased brain oxidative stress markers and reduced antioxidant enzymes compared to controls (p < 0.05). AECEL and DPZ administration significantly reduced brain oxidative stress markers and reduced antioxidant enzymes, as well as tumor necrosis factor-α and interleukin-6 levels (p < 0.05) compared to LPS ONLY group. Y-maze testing revealed decreased alternation (%) in the LPS group compared to controls (p < 0.05). Based on Y-maze performance, AECEL at 400 mg/kg emerged as the most effective dose, significantly improving alternation (%) compared to both LPS and LPS + DPZ groups (p < 0.05). Bielschowsky staining showed senile plaques and neurofibrillary tangles in the LPS group.ConclusionLPS induced PFC damage. Among the tested doses, AECEL at 600 mg/kg demonstrated the most effective improvement in cognitive function, memory, and anxiety-like behaviors as measured by the Y-maze test.

A-120 Analytical and Clinical Verification of the Elecsys® Alzheimer’s Disease Cerebrospinal Fluid Biomarkers pTau/Abeta42 and Total-Tau/Abeta42

Abstract Background Alzheimer’s disease (AD) is the most common form of dementia characterized by amyloid beta (Abeta) plaques and neurofibrillary tau tangles in the brain. Cerebrospinal fluid (CSF) biomarkers Abeta42, total tau (tTau), and phosphorylated tau (pTau181) offer a high degree of sensitivity and specificity in the diagnosis of AD and have utility in monitoring disease progression. AD biomarker ratios, pTau181/Abeta42 and tTau/Abeta42, correlate with amyloid positron emission tomography (PET) imaging, and several assays have received FDA clearance. This study was designed to evaluate the analytical performance and clinical utility of AD-related Abeta and tau biomarkers on the Roche cobas e601. Methods Precision studies were performed using Roche PreciControl kits. Intra- and inter-precision samples were tested ten times in a single day or twice a day for ten days, respectively. Five levels of Roche Calcheck material were measured in triplicate for linearity. Method comparison was carried out using 39 samples from the Elecsys CSF Correlation Sample Panel from Roche. Qualitative comparisons to amyloid PET Centiloid scores were performed using 35 CSF samples (n=11 PET negative, n=24 PET positive). CSF samples and PET interpretation were obtained from the Cleveland Clinic Institutional Review Board approved Cleveland Alzheimer's Disease Research Center (CADRC) and Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (LRCBH-Biobank). Results Conclusions Evaluation of AD biomarkers on the Roche cobas e601 revealed reliable precision and analytical accuracy. The pTau181/Abeta42 and tTau/Abeta42 ratios demonstrated excellent positive agreement when compared to amyloid PET, but poor negative agreement. This may be due to the small sample size of PET-negative patients. Alternatively, as amyloid PET detects neuritic plaque accumulation, the CSF biomarker-positive/PET-negative patients may have early non-neuritic amyloid plaque pathology not detectable by imaging. Overall, this assay is suitable for use and may serve as a valuable tool in AD diagnosis.

Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1. The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid β (Aβ) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheseshave been proposed, including the cholinergic, Aβ, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aβ hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

AlzDiscovery: A computational tool to identify Alzheimer's disease-causing missense mutations using protein structure information.

Alzheimer's disease (AD) is one of the most common forms of dementia and neurodegenerative diseases, characterized by the formation of neuritic plaques and neurofibrillary tangles. Many different proteins participate in this complicated pathogenic mechanism, and missense mutations can alter the folding and functions of these proteins, significantly increasing the risk of AD. However, many methods to identify AD-causing variants did not consider the effect of mutations from the perspective of a protein three-dimensional environment. Here, we present a machine learning-based analysis to classify the AD-causing mutations from their benign counterparts in 21 AD-related proteins leveraging both sequence- and structure-based features. Using computational tools to estimate the effect of mutations on protein stability, we first observed a bias of the pathogenic mutations with significant destabilizing effects on family AD-related proteins. Combining this insight, we built a generic predictive model, and improved the performance by tuning the sample weights in the training process. Our final model achieved the performance on area under the receiver operating characteristic curve up to 0.95 in the blind test and 0.70 in an independent clinical validation, outperforming all the state-of-the-art methods. Feature interpretation indicated that the hydrophobic environment and polar interaction contacts were crucial to the decision on pathogenic phenotypes of missense mutations. Finally, we presented a user-friendly web server, AlzDiscovery, for researchers to browse the predicted phenotypes of all possible missense mutations on these 21 AD-related proteins. Our study will be a valuable resource for AD screening and the development of personalized treatment.

Metabolic resistance of Aβ3pE-42, a target epitope of the anti-Alzheimer therapeutic antibody, donanemab.

The amyloid β peptide (Aβ), starting with pyroglutamate (pE) at position 3 and ending at position 42 (Aβ3pE-42), predominantly accumulates in the brains of Alzheimer's disease. Consistently, donanemab, a therapeutic antibody raised against Aβ3pE-42, has been shown to be effective in recent clinical trials. Although the primary Aβ produced physiologically is Aβ1-40/42, an explanation for how and why this physiological Aβ is converted to the pathological form remains elusive. Here, we present experimental evidence that accounts for the aging-associated Aβ3pE-42 deposition: Aβ3pE-42 was metabolically more stable than other Aβx-42 variants; deficiency of neprilysin, the major Aβ-degrading enzyme, induced a relatively selective deposition of Aβ3pE-42 in both APP transgenic and App knock-in mouse brains; Aβ3pE-42 deposition always colocalized with Pittsburgh compound B-positive cored plaques in APP transgenic mouse brains; and under aberrant conditions, such as a significant reduction in neprilysin activity, aminopeptidases, dipeptidyl peptidases, and glutaminyl-peptide cyclotransferase-like were up-regulated in the progression of aging, and a proportion of Aβ1-42 may be processed to Aβ3pE-42. Our findings suggest that anti-Aβ therapies are more effective if given before Aβ3pE-42 deposition.

Danggui Shaoyao San Alleviates Early Cognitive Impairment in Alzheimer's Disease Mice Through IRS1/GSK3β/Wnt3a-β-Catenin Pathway.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid plaques and neurofibrillary tangles. We explored the potential mechanism by which Danggui Shaoyao San (DSS) modulates central glucose metabolism via the insulin receptor substrate 1 (IRS1)/glycogen synthase kinase-3β (GSK3β)/Wnt3a-β-catenin pathway, thereby exerting protective effects on cognitive functions. In vitro, HT22 cells were induced with streptozotocin (STZ) to investigate the impact of GSK3β on pathway transduction. The active components in the DSS stock solution were validated using mass spectrometry. Subsequently, an AD model in C57BL/6J mice was established through STZ injection into both ventricles. The success of the model was validated behaviorally and pathologically. The Morris Water Maze (MWM) test, immunohistochemistry, Western blotting, quantitative reverse transcription-PCR, and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) were employed to evaluate the influence of DSS on memory and pathological changes in AD. The DSS stock solution, rich in active components, ameliorated the memory deficits in AD mice in the MWM. In vitro, GSK3β exhibited regulatory control over Wnt and β-catenin, with GSK3β inhibition mitigating β-amyloid and tau redundancies at protein and gene levels, facilitating signal transduction. In vivo, DSS impacted key targets in the IRS1/GSK3β/Wnt3a-β-catenin pathway, mitigated senile plaques resulting from amyloid β (Aβ) deposition and neurofiber tangles induced by tau hyperphosphorylation, and alleviated the decline in central glucose metabolism observed in FDG-PET. Our findings suggest that DSS potentially confers cognitive protection by alleviating central hypoglycemia through the IRS1/GSK3β/Wnt3a-β-catenin pathway. This may serve as a promising therapeutic avenue for AD.

Bacopa monnieri confers neuroprotection by influencing signaling pathways associated with interleukin 4, 13 and extracellular matrix organization in Alzheimer's disease: A proteomics-based perspective

Alzheimer's disease, a prevalent neurodegenerative disorder in the elderly, is characterized by the accumulation of senile plaques and neurofibrillary tangles, triggering oxidative stress, neuroinflammation, and neuronal apoptosis. Current therapies focus on symptomatic treatment rather than targeting the underlying disease-modifying molecular mechanisms and are often associated with significant side effects. Bacopa monnieri, a traditional Indian herb with nootropic properties, has shown promise in neurological disorder treatment from ancient times. However, its mechanisms of action in Alzheimer's disease remain elusive. In this study, a cellular model for Alzheimer's disease was created by treating differentiated IMR-32 cells with beta-amyloid, 1–42 peptide (Aβ42). Additionally, a recovery model was established through co-treatment with Bacopa monnieri to explore its protective mechanism. Co-treatment with Bacopa monnieri extract recovered Aβ42 induced damage as evidenced by the decreased apoptosis and reduced reactive oxygen species production. Mass spectrometry-based quantitative proteomic analysis identified 21,674 peptides, corresponding to 3626 proteins from the Alzheimer's disease model. The proteins dysregulated by Aβ42 were implicated in cellular functions, such as negative regulation of cell proliferation and microtubule cytoskeleton organization. The enriched pathways include extracellular matrix organization and interleukin-4 and interleukin-13 signaling. Bacopa monnieri co-treatment showed remarkable restoration of Aβ42 altered proteins, including FOSL1, and TDO2. The protein-protein interaction network analysis of Bacopa monnieri restored proteins identified the hub gene involved in Alzheimer's disease. The findings from this study may open up new avenues for creating innovative therapeutic approaches for Alzheimer's disease.

Gene deletion of Pregnancy-associated Plasma Protein-A (PAPP-A) improves pathology and cognition in an Alzheimer's disease mouse model

Alzheimer's disease (AD) is a progressive neurodegenerative disease of age with no effective preventative or treatment approaches. Deeper understanding of the mechanisms underlying the accumulation of toxic β-amyloid oligopeptides and the formation of amyloid plaque in AD has the potential to identify new therapeutic targets. Prior research links the insulin-like growth factor (IGF) system to pathologic mechanisms underlying AD. Suppression of local IGF-I receptor (IGFIR) signaling in AD mice has been shown to reduce plaque formation in the brain and delay neurodegeneration and behavioral changes. However, direct inhibitors of IGFIR signaling are not a viable treatment option for AD due to the essentiality of the IGFIR in physiological growth and metabolism. We have previously demonstrated a more selective means to reduce local IGFIR signaling through inhibition of PAPP-A, a novel zinc metalloprotease that regulates local IGF-I bioavailability through cleavage of inhibitory IGF binding proteins. Here we tested if deletion of PAPP-A in a mouse model of AD provides protection against pathology and behavioral changes. We show that compared to AD mice, AD/PAPP-A KO mice had significantly less plaque burden, reduced astrocytic activation, decreased IGF-IR activity, and improved cognition. Human senile AD plaques showed specific immunostaining for PAPP-A. Thus, inhibition of PAPP-A expression or activity may represent a novel treatment strategy for AD.

Understanding Osaka mutation polymorphic Aβ fibril response to static and oscillating electric fields: insights from computational modeling

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, impacting millions of individuals worldwide. Among its defining characteristics is the accumulation of senile plaques within the brain’s gray matter, formed through the self-assembly of misfolded proteins contributing to the progressive symptoms of AD. This study investigates a polymorphic Aβ fibril under static and oscillating electric fields using molecular dynamics simulation. Specifically, we utilized a polymorphic fibrillar complex composed of two intertwined pentamer-strands of the Aβ1–40 peptide with the Osaka mutation (E22Δ), known for its toxicity and stable structure. Our findings demonstrate that a 0.3 and 0.4 V/nm electric field combined with a 0.20 GHz frequency effectively disrupts the polymorphic conformation of Aβ fibrils. Furthermore, we elucidate the molecular mechanisms underlying this disruption, providing insights into the potential therapeutic use of oscillating electric fields for AD. This research offers valuable insights into novel therapeutic approaches for combating AD pathology.

Melatonin Supplementation Alleviates Impaired Spatial Memory by Influencing Aβ1-42 Metabolism via γ-Secretase in the icvAβ1-42 Rat Model with Pinealectomy

In the search for Alzheimer’s disease (AD) therapies, most animal models focus on familial AD, which accounts for a small fraction of cases. The majority of AD cases arise from stress factors, such as oxidative stress, leading to neurological changes (sporadic AD). Early in AD progression, dysfunction in γ-secretase causes the formation of insoluble Aβ1-42 peptides, which aggregate into senile plaques, triggering neurodegeneration, cognitive decline, and circadian rhythm disturbances. To better model sporadic AD, we used a new AD rat model induced by intracerebroventricular administration of Aβ1-42 oligomers (icvAβ1-42) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ1-42 + pin model experienced impaired spatial memory and increased Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβ1-42 or the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβ1-42 and γ-secretase levels in both structures. Our findings suggest that our icvAβ1-42 + pin model is extremely valuable for future AD research.

Levels of Amyloid Beta (Aβ) Expression in the Caenorhabditis elegans Neurons Influence the Onset and Severity of Neuronally Mediated Phenotypes.

A characteristic feature of Alzheimer's disease (AD) is the formation of neuronal extracellular senile plaques composed of aggregates of fibrillar amyloid β (Aβ) peptides, with the Aβ1-42 peptide being the most abundant species. These Aβ peptides have been proposed to contribute to the pathophysiology of the disease; however, there are few tools available to test this hypothesis directly. In particular, there are no data that establish a dose-response relationship between Aβ peptide expression level and disease. We have generated a panel of transgenic Caenorhabditis elegans strains expressing the human Aβ1-42 peptide under the control of promoter regions of two pan-neuronal expressed genes, snb-1 and rgef-1. Phenotypic data show strong age-related defects in motility, subtle changes in chemotaxis, reduced median and maximum lifespan, changes in health span indicators, and impaired learning. The Aβ1-42 expression level of these strains differed as a function of promoter identity and transgene copy number, and the timing and severity of phenotypes mediated by Aβ1-42 were strongly positively correlated with expression level. The pan-neuronal expression of varying levels of human Aβ1-42 in a nematode model provides a new tool to investigate the in vivo toxicity of neuronal Aβ expression and the molecular and cellular mechanisms underlying AD progression in the absence of endogenous Aβ peptides. More importantly, it allows direct quantitative testing of the dose-response relationship between neuronal Aβ peptide expression and disease for the first time. These strains may also be used to develop screens for novel therapeutics to treat Alzheimer's disease.