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

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12311 - 12311

Published: Nov. 16, 2024

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

Language: Английский

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Telmisartan Reduces LPS-Mediated Inflammation and Induces Autophagy of Microglia

Neuroglia, Journal Year: 2024, Volume and Issue: 5(2), P. 182 - 201

Published: June 20, 2024

Background: Chronic neuroinflammation mediated by persistent microglial activation is strongly linked to neurodegeneration. Therefore, targeting could be beneficial in treating neurodegenerative disorders. Angiotensin receptor blockers (ARBs), commonly prescribed for high blood pressure, exhibit prominent anti-inflammatory effects the brain and are considered potential therapies diseases neurotrauma. Although all ARBs angiotensin II type I antagonists, some act through other signaling pathways, allowing multiple mechanisms of action. The not well understood. Methods: In this study, we compared eight different FDA-approved their ability reduce LPS stimulation primary microglia or BV2 cells analyses nitric oxide production, reactive oxygen species generation, mRNA proinflammatory cytokines. Finding specific unique telmisartan, interrogated pathways downstream effectors telmisartan activity on microglia. Results: Our findings indicate that showed greatest efficacy reducing induction (ROS) production Uniquely amongst ARBs, activated AMPK phosphorylation inhibited mTOR phosphorylation. Telmisartan’s was partially inhibitor compound C. Furthermore, uniquely induced markers autophagy an AMPK–mTOR–autophagy pathway. Telmisartan also reduced viability. cytotoxicity ameliorated a pan-caspase inhibitor, indicating link between apoptosis. Conclusions: We conclude has properties relative including potent actions autophagy, which may enable therapeutic uses.

Language: Английский

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Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13450 - 13450

Published: Dec. 15, 2024

The overlapping molecular pathophysiology of Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph 33+ million biomedical journal articles. unsupervised learning rank aggregation algorithm SemNet 2.0 compared the most important amino acid, peptide, protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% its with ALS AD; AD 64.2% ALS; 68.3% results were validated mapped functional biological processes supervised human supervision an external large language model. overall percentages intersecting as follows: inflammation immune response, 19%; synapse neurotransmission, cell cycle, 15%; aggregation, 12%; membrane regulation, 11%; stress response 9%; gene 4%. Once normalized for node count, mappings cycle regulation more prominent in intersection Protein energetics Synapse greater at ALS. Given extensive overlap, small differences genetic, environmental factors likely shape underlying expressed disease phenotype. help prioritize testable hypotheses future clinical experimental research.

Language: Английский

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