Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 16, 2022

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.

Language: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update

Journal of Biomedical Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: Oct. 2, 2023

Abstract Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis AD involves various pathophysiological events, including accumulation amyloid and tau, neuro-inflammation, neuronal injury. Clinical trials focusing on new drugs for were documented in 2020, but subsequent developments have emerged since then. Notably, US-FDA has approved Aducanumab Lecanemab, both antibodies targeting amyloid, marking end nearly two-decade period without drugs. In this comprehensive report, we review all listed clinicaltrials.gov, elucidating their underlying mechanisms study designs. Ongoing clinical are investigating numerous promising AD. main trends these involve pathophysiology-based, disease-modifying therapies recruitment participants earlier stages disease. These underscore significance conducting fundamental research pathophysiology, prevention, intervention prior to occurrence brain damage caused by

Language: Английский

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Tau-targeting therapies for Alzheimer disease: current status and future directions

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(12), P. 715 - 736

Published: Oct. 24, 2023

Language: Английский

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Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(7), P. 963 - 974

Published: May 25, 2023

Language: Английский

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Engineered Extracellular Vesicles with SHP2 High Expression Promote Mitophagy for Alzheimer's Disease Treatment

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(49)

Published: Oct. 4, 2022

Mitochondrial dysfunction is a fundamental pathological feature of Alzheimer's disease (AD). However, toxicity and poor brain enrichment existing mitophagy inducers limit their further applications. In this study, platform for AD therapy developed using nanosized mesenchymal-stem-cells-derived extracellular vesicles with tyrosine phosphatase-2 (SHP2) high-expression (MSC-EVs-SHP2). The high blood-brain barrier penetration ability MSC-EVs-SHP2 demonstrated in AD-mice, facilitating SHP2 delivery to the brain. addition, significantly induces neuronal cells, which alleviates mitochondrial damage-mediated apoptosis NLRP3 inflammasome activation. Mitophagy diminishes cells neuroinflammation, culminating rescued synaptic loss cognitive decline an mouse model. EV-engineering technology provides potential effective by inducing mitophagy.

Language: Английский

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Compilation of reported protein changes in the brain in Alzheimer’s disease

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 25, 2023

Abstract Proteomic studies of human Alzheimer’s disease brain tissue have potential to identify protein changes that drive disease, and new drug targets. Here, we analyse 38 published proteomic studies, generating a map in across thirteen regions, three stages (preclinical mild cognitive impairment, advanced disease), proteins enriched amyloid plaques, neurofibrillary tangles, cerebral angiopathy. Our dataset is compiled into searchable database (NeuroPro). We found 848 were consistently altered 5 or more studies. Comparison early-stage revealed associated with synapse, vesicle, lysosomal pathways show change early but widespread mitochondrial expression are only seen disease. Protein similar for regions considered vulnerable resistant. This resource provides insight highlights interest further study.

Language: Английский

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Emerging degrader technologies engaging lysosomal pathways

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(21), P. 8832 - 8876

Published: Jan. 1, 2022

ATTECs and several other emerging degrader technologies hijacking the lysosomal pathways greatly expand spectrum of degradable targets provide new opportunities for targeted drug discovery.

Language: Английский

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Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 103 - 197

Published: Oct. 16, 2023

Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, it seems to link different hypotheses mechanisms of AD neuropathology high fidelity. The particularly vulnerable damage, mainly because its unique lipid composition, resulting an amplified cascade redox reactions that target several cellular components/functions ultimately leading neurodegeneration. present review highlights the “OS hypothesis AD,” including amyloid beta-peptide-associated role protein oxidation unraveled by proteomics, antioxidant strategies have been investigated modulate progression AD. Collected studies from our groups others contributed unraveling close relationships between perturbation homeostasis elucidating redox-regulated events potentially involved both pathogenesis However, complexity requires in-depth understanding intracellular affecting relevant for functions. This crucial developing pharmacological targeting OS-mediated toxicity may contribute slow well improve quality life persons this severe dementing disorder.

Language: Английский

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Oral feeding of nanoplastics affects brain function of mice by inducing macrophage IL-1 signal in the intestine

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112346 - 112346

Published: April 1, 2023

Nanoplastics (NPs) as contaminants in food and water have drawn increasing public attention. However, little is known about how NPs shape the gut immune landscape after injection. In this study, we fabricate (∼500 nm) microplastics (MPs) (∼2 μm) evaluate their vivo effects by feeding them to mice. The results suggest that show a better ability induce macrophage activation than MPs. addition, trigger interleukin-1 (IL-1)-producing reprogramming via inducing lysosomal damage. More importantly, IL-1 signaling from intestine can affect brain immunity, leading microglial Th17 differentiation, all of which correlates with decline cognitive short-term memory NP-fed Thus, study provides insight into mechanism action gut-brain axis, delineates way reduce function, highlights importance fixing plastic pollution problem worldwide.

Language: Английский

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