Accumulation Of Plaques Research Articles

Prospective use of miRNAs as biomarkers in the diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in the aging population. Pathogenic processes related to the accumulation of amyloid plaques (Aβ) and intracellular neurofibrillary tangles (NFTs) begin during the asymptomatic stage long before the onset of deterioration in cognitive functions and neurodegeneration, which makes rapid diagnosis and treatment difficult. Although biochemical diagnostic markers isolated from the body fluids of AD patients are currently used, scientists are engaged in research into molecular biomarkers that will significantly accelerate the diagnosis long before the first clinical symptoms appear. The research presented here focused on microRNAs (miRNAs), small, non-coding RNA molecules that are involved in the regulation of the post-transcriptional expression of many genes. A review of the literature revealed that miRNAs play an important role in regulating the expression of genes involved in the pathophysiological mechanisms of AD. Changes in the levels of miRNAs in a patient's body fluids can be used for rapid diagnosis. Original scientific articles published between 2014 and 2023 describing clinical and experimental studies on the role and expression levels of various miRNAs were selected from scientific databases such as PubMed, NCBI, Science Direct, and Google Scholar. The selected miRNAs were divided into 2 groups based on their expression level in AD: those with increased expression and those with decreased expression. A review of the latest scientific reports confirms that miRNAs may be a promising source of non-invasive and widely available biomarkers. Additionally, their modulation may prove to be an effective therapeutic strategy in AD.

Pathology and Treatments of Alzheimer’s Disease Based on Considering Changes in Brain Energy Metabolism Due to Type 2 Diabetes

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cognitive dysfunction, memory decline, and behavioral disturbance, and it is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Although various hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid beta hypothesis, oxidative stress hypothesis, and abnormal phosphorylation of tau proteins, the exact pathogenic mechanisms underlying AD remain largely undefined. Furthermore, effective curative treatments are very limited. Epidemiologic studies provide convincing evidence for a significant association between type 2 diabetes and AD. Here, we showed energy metabolism using glucose, lactate, ketone bodies, and lipids as energy substrates in a normal brain, and changes in such energy metabolism due to type 2 diabetes. We also showed the influences of such altered energy metabolism due to type 2 diabetes on the pathology of AD. Furthermore, we comprehensively searched for risk factors related with type 2 diabetes for AD and showed possible therapeutic interventions based on considering risk factors and altered brain energy metabolism due to type 2 diabetes for the development of AD.

The Therapeutic Potential of Targeting the Pd-L1/Pd-1 Immune Checkpoint Pathway in Alzheimer's Disease

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, neurofibrillary tangles, and chronic neuroinflammation. Emerging evidence suggests that the PD-L1/PD-1 immune checkpoint pathway plays a critical role in modulating neuroinflammation, microglial function, and amyloid-β clearance in AD. This review summarizes the current understanding of the PD-L1/PD-1 pathway in AD and discusses its potential as a therapeutic target. Preclinical studies and clinical trials have demonstrated that targeting the PD-L1/PD-1 axis can enhance microglial phagocytosis, promote amyloid-β clearance, and reduce neuroinflammation. We examine the potential benefits and challenges of using existing immunotherapy drugs, such as anti-PD-L1 and anti-PD-1 antibodies, in the context of AD. Additionally, we explore the development of novel, more specific agents targeting the PDL1/ PD-1 pathway, as well as potential synergistic approaches with other immunomodulatory or amyloid-β-targeting treatments. This review provides a comprehensive and up-to-date analysis of the PD-L1/PD-1 immune checkpoint pathway's role in Alzheimer's disease, highlighting its promising therapeutic potential for improving patient outcomes. Further research is warranted to optimize treatment strategies and evaluate the long-term safety and efficacy of targeting this axis in clinical settings.

The analysis of whether CRISPR-Cas9 is the way forward for Alzheimers disease treatment

Alzheimer's disease (AD) is a progressive and irreversible neurological condition which according to WHO affects more than 55 million individuals globally and is the leading cause of dementia and thereby poses a significant burden on healthcare systems worldwide. AD progresses through stages of mild cognitive impairment to severe dementia and is characterised by the accumulation of extracellular amyloid-beta plaques and neurofibrillary tangles concentrated with tau proteins in neocortical structures and the temporal lobe. Gene-editing technology such as the most prevalent CRISPR-Cas9 provides prospects for the treatment of AD by enabling precise modifications of the genetic mutations associated with the disease. This review explores the potential of CRISPR-Cas9 to revolutionise treatment by targeting and rectifying mutated genes but also examines the current state of Alzheimers treatment. This paper examines recent advancements in preclinical studies and highlights the successes in reducing amyloid-beta plaques and tau neurofibrillary tangles, the pathological features of AD. By evaluating current CRISPR-Cas9 research and other treatments for AD, I aim to provide insight into its potential as a transformative gene therapy approach whilst evaluating its limitations.

Diagnosing Alzheimer Disease

ABSTRACT OBJECTIVE This article reviews the current understanding of Alzheimer disease (AD), including the natural history, common risk factors, and expected progression of AD neuropathologic change so that neurologists can apply this knowledge to identify patients with symptoms, signs, and findings on common diagnostic tests consistent with AD. LATEST DEVELOPMENTS The advent of potential disease-modifying therapies emphasizes the need to develop and deploy a practical and efficient approach to diagnose patients with cognitive impairment due to AD. ESSENTIAL POINTS The accumulation and spread of cerebral amyloid plaques and tau tangles in patients with AD leads to synaptic dysfunction, neuronal loss, and the eventual emergence and progression of cognitive impairment. A pragmatic and organized approach is needed to recognize patients with symptomatic AD in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making.

From Fundamentals to Innovation in Alzheimer's Disease: Molecular Findings and Revolutionary Therapies.

Alzheimer's disease (AD) is a global health concern and the leading cause of dementia in the elderly. The prevalence of this neurodegenerative condition is projected to increase concomitantly with increased life expectancy, resulting in a significant economic burden. With very few FDA-approved disease-modifying drugs available for AD, there is an urgent need to develop new compounds capable of impeding the progression of the disease. Given the unclear etiopathogenesis of AD, this review emphasizes the underlying mechanisms of this condition. It explores not only well-studied aspects, such as the accumulation of Aβ plaques and neurofibrillary tangles, but also novel areas, including glymphatic and lymphatic pathways, microbiota and the gut-brain axis, serotoninergic and autophagy alterations, vascular dysfunction, the metal hypothesis, the olfactory pathway, and oral health. Furthermore, the potential molecular targets arising from all these mechanisms have been reviewed, along with novel promising approaches such as nanoparticle-based therapy, neural stem cell transplantation, vaccines, and CRISPR-Cas9-mediated genome editing techniques. Taking into account the overlap of these various mechanisms, individual and combination therapies emerge as the future direction in the AD strategy.

Integration of Single-Cell and Spatial Transcriptomic Data Reveals Spatial Architecture and Potential Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the gradual loss of neurons and the accumulation of amyloid plaques and neurofibrillary tangles. Despite advancements in the understanding of AD's pathophysiology, the cellular organization and interactions in the prefrontal cortex (PFC) remain elusive. Eight single-cell RNA sequencing (scRNA-seq) datasets from both normal controls and individuals with AD were harmonized. Stringent preprocessing protocols were implemented to uphold dataset integrity. Unsupervised clustering and annotation revealed 22 distinct cell clusters corresponding to 19 unique cell types. The spatial architecture of the PFC region was constructed using the CARD tool. Further analyses encompassed trajectory examination of Oligodendrocyte subtypes, evaluation of regulon activity scores, and spot clustering within white matter regions (WM). Differential expression analysis and functional enrichment assays unveiled molecular signatures linked to AD progression and were validated using microarray data sourced from neurodegenerative disorder patients. Our investigation employs scRNA-seq and spatial transcriptomics to uncover the cellular atlas and spatial architecture of the human PFC in AD. Moreover, our results indicate that Oligodendrocytes are more prevalent in AD patients, showcasing diverse subtypes and spatial organization within WM regions. Each subtype appears to be associated with distinct biological processes and transcriptional regulators, shedding light on their involvement in AD pathology. Notably, the Oligodendrocyte_C6 subtype is linked to neurological damage in AD patients, characterized by heightened expression of genes involved in cell-cell connections, cell membrane stability, and myelination. Additionally, 12 target genes regulated by NFIA were identified, which are upregulated in AD patients and associated with disease progression. Elevated PLXDC2 expression in peripheral blood was also identified, suggesting its potential as a non-invasive biomarker for early AD detection. Our study provides novel insights into the role of Oligodendrocytes in AD and highlights the potential of PLXDC2 as a blood biomarker for non-invasive diagnosis and monitoring of AD patients.

Amyloid beta-activated alpha-1-syntrophin has ramifications on Rac1 activation, ROS production and neuronal cell death.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of β-amyloid (Aβ)-containing extracellular neuritic plaques and phosphorylated tau-containing intracellular neurofibrillary tangles. It remains the primary neuropathological criteria for the diagnosis of AD. Additionally, several other processes are currently being recognized as significant risk factors for AD development, including the brain's susceptibility to reactive oxygen species (ROS). The ROS production is among the early signs in the progression of AD. However, the underlying mechanisms behind increased ROS production in AD remain poorly understood. We have observed SNTA1 plays critical role in regulating ROS levels in different pathological conditions. Here, we wanted to gain further insight into the role of SNTA1 in the development of AD by using IMR32 cell line. Our results show that the accumulation of Aβ plaques in Alzheimer's model neuroblastoma cells significantly increases the expression and activation of SNTA1 and MKK6 kinase. The activation of MKK6 results in the phosphorylation of SNTA1, creating a binding site for Rac1, leading to its activation and subsequent production of ROS. Excessive ROS production leads to cell cycle arrest in the G2/M phase, a hallmark of AD. Our study provides new insight into the mechanism of Aβ-mediated cell death in AD and suggests that MKK6-mediated activation of alpha-1-syntrophin promotes ROS production in neuronal cells, resulting in cell death. This study presents a mechanistic insight into Aβ-mediated cell death and could serve as a paradigm for reducing neuronal cell death in AD.

Amyloid-beta antibody treatment in Alzheimer's disease : An update on recent data and outlook on implementation in clinical routine.

Amyloid-beta (Aβ) antibody treatment has emerged as apromising approach for the treatment of Alzheimer's disease (AD), targeting the accumulation of Aβ plaques, which are ahallmark of the disease. This review provides an update on recent clinical trial data, highlighting the efficacy and safety of various antibodies targeting Aβ. Recent trials have demonstrated that certain Aβ antibodies can reduce amyloid plaques and slow cognitive decline in patients with early AD. Key findings from trials of drugs are discussed, including their mechanisms of action, dosing regimens, and observed side effects. The potential for Aβ antibody therapy to be integrated into routine clinical practice is also explored. While Aβ antibody therapy represents asignificant advancement in AD treatment, ongoing research is needed to optimize their use and understand their long-term impact. This review underscores the importance of personalized medicine in AD and the need for continued innovation in therapeutic strategies.

Lecanemab for Alzheimer's Disease

Lecanemab is a novel drug developed by Sisai and Biogen aimed at treating Alzheimer’s Disease. Alzheimer’s Disease is characterized by the misfolding and accumulation of neurotoxic amyloid-beta plaques in the brain, leading to neuronal cell death and brain shrinkage. Lecanemab contains monoclonal antibodies that have a high affinity for soluble and insoluble forms of amyloid-beta peptides. These antibodies bind, neutralize, and eliminate amyloid-beta aggregates to slow Alzheimer’s Disease progression.2 Phase II dose-finding trial for Lecanemab conducted with 854 participants with early Alzheimer’s Disease demonstrated no significant difference between Lecanemab and placebo groups at the 12-month mark. However, a 27% reduction in clinical decline in the Lecanemab group was seen after 18 months compared to the placebo group. Adverse effects of Lecanemab include transient fever and asymptomatic fluid formation in the brain. The drug was approved by the Food and Drug Administration and launched in the United States on January 18, 2023. Manufacturing and marketing applications for Lecanemabwere also recently submitted in Europe, Japan, and Canada1 With FDA approval, the drug is currently priced at 26,500 USD per year, with Medicare pledging to cover 80% of the cost.3

Salidroside Ameliorates Macrophages Lipid Accumulation and Atherosclerotic Plaque by Inhibiting Hif-1α-Induced Pyroptosis

BackgroundHipoxia-inducible factor 1 alpha (Hif-1α) is a significant risk factor for atherosclerotic cardiovascular disease. Salidroside (SAL) has demonstrated anti-oxidative and anti-cardiovascular disease effects. Currently, there are no relevant studies investigating the interaction between SAL and Hif-1α in the progression of atherosclerosis . MethodsHif-1α was either knocked down or upregulated in Ana-1 macrophages-derived foam cells, and atherosclerosis ApoE−/− mice were treated with or without SAL. A Protein-protein network involving Hif-1α and pyroptosis-related genes was identified through bioinformatic analysis and validated in human vascular tissues. The Oil Red O and DiI staining were used to detect the intracellular ox-LDL accumulation. The HE and Oil Red O staining were employed to evaluate atherosclerotic plaque in vivo. The levels of relevant molecules were quantified using WB, qRT-PCR, ELISA, and immunohistochemistry. The target proteins of SAL were identified through Molecular docking and Cell Thermal Shift Assay (CESTA). ResultsBoth Hif-1α knockdown and SAL treatment markedly reduced lipid accumulation in macrophages-derived foam cells. Hif-1α was closely associated with Caspase1, Gsdmd, NRLP3, and IL-1β, and co-located in CD86+ macrophages-derived foam cells within atherosclerotic plaque. SAL inhibited Hif-1α-induced Caspase-1-dependent pyroptosis and lipid accumulation by directly bonding to Hif-1α. In vivo, SAL treatment decreased atherosclerotic plaque and improved plasma lipid profiles. Furthermore, SAL reduced M1 macrophages infiltration and the levels of Hif-1α, C-Caspase1, Gsdmd-N, NRLP3, IL-18, and IL-1β in atherosclerotic plaque. ConclusionSAL alleviated the lipid accumulation in macrophages and atherosclerotic plaques by inhibiting pyroptosis pathway via directly binding to Hif-1α, which may be a promising therapeutic strategy for AS treatment.

PERFIL DE PACIENTES SUBMETIDOS A TOMOGRAFIA DE CORONÁRIAS EM UM SERVIÇO DE IMAGEM CARDIOVASCULAR DE SERGIPE

Introduction: Computed tomography angiography (CT angiography) of the coronary arteries can identify coronary artery disease (CAD) in its early stages. CAD is characterized by a narrowing of the arterial lumen due to the accumulation of fatty plaques in its walls. Currently, the gold standard for diagnosis is coronary angiography, an invasive measure that seeks to visualize the arterial lumen. The aim of this study was to characterize an outpatient sample using CT angiography as a diagnostic method. Methodology: This cross-sectional, observational prevalence study was based on data collection at a clinic in the city of Aracaju, where the angiotomography results of 210 patients were analyzed, 115 females and 95 males, tabulated as absolute numbers, percentages and averages. Results: The correlation of gender and age with the presence of luminal reduction showed that men and older individuals had a higher degree of alterations on CT angiography. When assessed by territory, the Left Coronary Trunk (LCT) often showed no luminal reduction, with the Anterior Descending Trunk showing the most alterations. Men present more lesions in the Right Coronary and Anterior Descending. Conclusion: Several factors can influence the incidence of CAD, gender and age being among the most important, as shown by the higher incidence in older men than in women or in younger individuals with luminal reduction.

Inhibition of ceramide de novo synthesis mitigates atherosclerosis

Abstract Background Atherosclerosis is the primary underlying cause of cardiovascular disease. Plasma ceramides are positively correlated with an increased risk of major adverse cardiovascular events and serve as an alternative biomarker for cardiovascular disease. Importantly, ceramide levels are notably higher within atherosclerotic plaques. Therefore, inhibiting the ceramide de novo synthesis pathway in the plaques may serve as a potential therapeutic intervention for atherosclerosis. Purpose We aim to assess the therapeutic efficacy of a nano-formulation of myriocin, a targeted inhibitor of serine-palmitoyl transferase, the key enzyme in ceramide de novo synthesis, in treating atherosclerosis. Methods Myriocin was encapsulated within the hydrophobic core of lipid-based nanoparticles specifically designed for this study. Male and female ApoE-/- mice, subjected to an 8-week high-fat diet regimen, received either myriocin nanoparticles (treatment group) or empty nanoparticles (control group) intravenously once a week for 4 weeks at a dose of 1.3 mg/kg body weight while still on the high-fat diet. At the study endpoint, whole aortas were harvested and subjected to Oil Red O staining to quantify the total lesion area. Histological staining was performed on serial sections of the aortic root to analyze the cellular composition within the plaques. Plasma samples were collected for total cholesterol measurement and lipidomic analysis. Results Upon intravenous administration, myriocin nanoparticles exhibited preferential accumulation in atherosclerotic plaques. Compared to control mice, those treated with myriocin nanoparticles exhibited a 58.7% reduction in total lesion area in male ApoE-/- mice and a 64.6% reduction in female ApoE-/- mice (p<0.0001). Consistently, the lesion areas in the aortic root were also reduced in the treated mice. Notably, myriocin nanoparticles enhanced collagen and alpha-smooth muscle content, while reducing macrophages and neutral lipids within the plaques, leading to a reduced plaque vulnerability index and preventing rupture events. TUNEL staining revealed reduced cellular apoptosis in the atherosclerotic plaques, resulting in a smaller necrotic area in the treated mice. In vitro experiments demonstrated that myriocin nanoparticles effectively inhibited lipopolysaccharide-induced inflammatory response and oxidative stress in bone marrow-derived macrophages. Furthermore, myriocin nanoparticles restored the gene expression of enzymes involved in the fatty acid beta-oxidation pathway, such as ACOX1 and CPT1A, in foam cells. Conclusion Using myriocin nanoparticles to inhibit excessive ceramide production due to inflammation reduces inflammation, and ROS production, while restoring fatty acid beta-oxidation in macrophages. This approach emerges as an effective strategy for targeting ceramide de novo synthesis within atherosclerotic plaques, thereby mitigating atherosclerosis progression and improving plaque stability.

β-Amyloid impairs Proteasome structure and function. Proteasome activation mitigates amyloid induced toxicity and cognitive deficits.

Alzheimer's Disease (AD) is the leading cause of dementia globally, affecting around 50 million people and marked by cognitive decline and the accumulation of β-amyloid plaques and hyperphosphorylated tau. The limited treatment options and numerous failed clinical trials targeting β-amyloid (Aβ) highlight the need for novel approaches. Lowered proteasome activity is a consistent feature in AD, particularly in the hippocampus. Impaired proteasome function in AD is hypothesized to stem from direct inhibition by β-amyloid or hyperphosphorylated tau, disrupting critical neuronal processes such as memory formation and synaptic plasticity. This study tests the hypothesis that AD related deficits are driven in part by impaired proteasome function as a consequence of inhibition by Aβ. We evaluated how proteasome function is modulated by Aβ and the capacity of two proteasome-activating compounds, TAT1-8,9-TOD and TAT1-DEN to rescue Aβ-induced impairment in vitro, as well as survival deficits in cell culture and Aβ-induced cognitive deficits in Drosophila and mouse models. Our study demonstrates that oligomeric β-amyloid binds to the 20S proteasome and impairs its activity and conformational stability. The oligomers also destabilize the 26S proteasome to release the free 20S proteasome. Treatment with proteasome activators TAT1-8,9TOD and TAT1-DEN rescue the 20S proteasome function and reduces cell death caused by Aβ42 toxicity in SK-N-SH cells. In Drosophila models overexpressing Aβ42, oral administration of proteasome agonists delayed mortality and restored cognitive function. Chronic treatment with TAT1-DEN protected against deficits in working memory caused by Aβ42 in mice and in hAPP(J20) mice with established deficits, acute TAT1-DEN treatment significantly improved spatial learning, with treated mice performing comparably to controls. Aβ has dual impacts on 20S and 26S proteasome function and stability. Proteasome activation using TAT1-8,9TOD and TAT1-DEN shows promise in mitigating AD-like deficits by protecting against amyloid toxicity and enhancing proteasome function. These findings suggest that targeting proteasome activity could be a viable therapeutic approach for AD, warranting further investigation into the broader impacts of proteasome modulation on AD pathology.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

Novel Piperazine Based Compounds Target Alzheimer's Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein.

Alzheimer's disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ1-42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ1-42 as well as dissociation of preformed aggregates from these peptides. Compounds D-687 and D-688 reversed Aβ1-42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with Drosophila melanogaster expressing human tau protein isoform (2N4R) in all the neurons, compound D-688 significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.

Natural Compounds as Inhibitors of Aβ Peptide and Tau Aggregation.

Neurodegenerative conditions like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) encompass disorders characterized by the degeneration of neurons in specific circumstances. The quest for novel agents to influence these diseases, particularly AD, has unearthed various natural compounds displaying multifaceted activities and diverse pharmacological mechanisms. Given the ongoing extensive study of pathways associated with the accumulation of neurofibrillary aggregates and amyloid plaques, this paper aims to comprehensively review around 130 studies exploring natural products. These studies focus on inhibiting the formation of amyloid plaques and tau protein tangles, with the objective of potentially alleviating or delaying AD.

PPARs (Peroxisome Proliferator-activated Receptors) and Their Agonists in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid β (Aβ) aggregation, tau aggregates, and neurofibrillary tangles. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported recently with neuroprotective and anti-inflammatory properties. PPARs belong to the superfamily of nuclear hormone receptors and function as ligand-activated transcription factors. These have emerged as crucial players in the pathogenesis of AD. This review presented the potential of PPARs and their agonists in treating neurodegenerative diseases like AD. <P> </P> PPARs regulate the expression of specific genes vital for synaptic function and neurotransmitter release. PPAR agonists play a critical role in increasing the clearance of Aβ peptides by lowdensity lipoprotein receptor-related protein 1 (LRP1) in the microvascular endothelial cells of the human brain. Studies have shown that PPAR agonists reduce the level of APoE-mRNA, contributing to the accumulation of Aβ plaques and up-regulation of PPAR. A knockout of miR-128 has been found to inhibit AD-like cognitive decline, amyloid precursor protein (APP) amyloidogenic processing, and inflammatory responses in AD. <P> </P> PPARs are involved in the pathomechanism of AD, and therefore, PPAR agonists could be viable options for controlling the neurodegenerative symptoms and may be useful in treating AD.

Expressing miR-282 mitigates Aβ42-induced neurodegeneration in Alzheimer's model in Drosophila

Alzheimer's disease is a complex neurodegenerative condition characterized by the accumulation of amyloid beta plaques, leading to memory loss, cognitive decline, and impaired autonomous behavior. Despite extensive research, an effective treatment remains elusive. The buildup of amyloid beta plaques (Aβ42) in the brain causes oxidative stress and disrupts normal molecular signaling, adversely affecting neuron function. Previous research has identified factors that can either exacerbate or mitigate neurodegenerative diseases. Our study aimed to uncover new factors involved in the pathogenesis of Alzheimer's disease. Using Drosophila as a model organism, we employed the Gal4/UAS system to express human Aβ42 in the flies' retinal neurons which led to neurodegenerative changes in their compound eyes. To identify genetic modifiers, we conducted a screen by co-expressing microRNAs and found that miR-282 acts as a suppressor. Overexpressing miR-282 in the GMR > Aβ42 background reduced Aβ42-induced neurodegeneration. Further analysis using prediction tools and RNA interference experiments identified three potential downstream targets of miR-282: calpain-B, knot, and scabrous. Downregulating these genes via RNA interference in the GMR > Aβ42 background mitigated neurodegeneration. Our research highlights miR-282 as a novel molecule that may influence the progression of Alzheimer's disease, offering potential avenues for future therapeutic or diagnostic developments.

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.