Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

et al.

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

Hallmarks of neurodegenerative diseases DOI Creative Commons

David M. Wilson,

Mark Cookson, Ludo Van Den Bosch

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(4), P. 693 - 714

Published: Feb. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Language: Английский

Citations

790
Alzheimer's disease drug development pipeline: 2022 DOI Creative Commons
Jeffrey L. Cummings, Garam Lee,

Pouyan Nahed

et al.

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2022, Volume and Issue: 8(1)

Published: Jan. 1, 2022

Alzheimer's disease (AD) represents a global health crisis. Treatments are needed to prevent, delay the onset, slow progression, improve cognition, and reduce behavioral disturbances of AD. We review current clinical trials drugs in development for treatment

Language: Английский

Citations

535
Alzheimer's disease drug development pipeline: 2021 DOI Creative Commons
Jeffrey L. Cummings, Garam Lee,

Kate Zhong

et al.

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2021, Volume and Issue: 7(1)

Published: Jan. 1, 2021

Abstract Introduction The number of individuals worldwide with Alzheimer's disease (AD) is growing at a rapid rate. New treatments are urgently needed. We review the current pipeline drugs in clinical trials for treatment AD. Methods interrogated ClinicalTrials.gov, federal registry to identify trials. Results There 126 agents 152 assessing new therapies AD: 28 Phase 3 trials, 74 2, and 24 1. majority (82.5%) target underlying biology AD intent modification; 10.3% putative cognitive enhancing agents; 7.1% being developed reduce neuropsychiatric symptoms. Discussion This analysis shows that biological processes more diversified, biomarkers regularly used, repurposed explored determine their utility

Language: Английский

Citations

418
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets DOI Creative Commons
Chao Gao, Jingwen Jiang, Yuyan Tan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Language: Английский

Citations

418
The sirtuin family in health and disease DOI Creative Commons
Qi‐Jun Wu, Tie‐Ning Zhang,

Huanhuan Chen

et al.

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

Published: Dec. 29, 2022

Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, involved numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles members SIRT family health disease conditions. Notably, this protein plays a variety important cellular biology such as inflammation, metabolism, oxidative stress, apoptosis, etc., thus, it is considered potential therapeutic target for different kinds pathologies including cancer, cardiovascular disease, respiratory other Moreover, identification modulators exploring functions these prompted increased efforts discover new small molecules, which can modify activity. Furthermore, several randomized controlled trials indicated that interventions might affect expression human samples, supplementation diverse impact on physiological function participants. In review, we introduce history structure family, discuss molecular mechanisms elaborate regulatory SIRTs summarize inhibitors activators, review related clinical studies.

Language: Английский

Citations

400
Blood-based biomarkers for Alzheimer's disease: towards clinical implementation DOI
Charlotte E. Teunissen, Inge M.W. Verberk, Elisabeth H. Thijssen

et al.

The Lancet Neurology, Journal Year: 2021, Volume and Issue: 21(1), P. 66 - 77

Published: Nov. 25, 2021

Language: Английский

Citations

356
The probabilistic model of Alzheimer disease: the amyloid hypothesis revised DOI
Giovanni B. Frisoni, Daniele Altomare, Dietmar Rudolf Thal

et al.

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 23(1), P. 53 - 66

Published: Nov. 23, 2021

Language: Английский

Citations

328
Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials DOI
Rik Ossenkoppele, Rik van der Kant, Oskar Hansson

et al.

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 21(8), P. 726 - 734

Published: May 25, 2022

Language: Английский

Citations

279
Nutrition, Physical Activity, and Other Lifestyle Factors in the Prevention of Cognitive Decline and Dementia DOI Open Access
Ligia J. Domínguez, Nicola Veronese,

Laura Vernuccio

et al.

Nutrients, Journal Year: 2021, Volume and Issue: 13(11), P. 4080 - 4080

Published: Nov. 15, 2021

Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for impairment and dementia is advanced age followed by other determinants such genetic, socioeconomic, environmental factors, including nutrition physical activity. In the next decades, a rise in cases expected due largely aging of world population. There no hitherto effective pharmaceutical therapies treat age-associated dementia, which underscores crucial role prevention. A relationship among diet, activity, lifestyle with function has been intensively studied mounting evidence supporting these development decline chief cause disability globally. Several dietary patterns, foods, nutrients have investigated this regard, some encouraging disappointing results. This review presents current effects components, supplements, sleep social engagement on prevention or delay onset age-related dementia.

Language: Английский

Citations

265
Impact of Mediterranean Diet on Chronic Non-Communicable Diseases and Longevity DOI Open Access
Ligia J. Domínguez,

Giovanna Di Bella,

Nicola Veronese

et al.

Nutrients, Journal Year: 2021, Volume and Issue: 13(6), P. 2028 - 2028

Published: June 12, 2021

The average life expectancy of the world population has increased remarkably in past 150 years and it is still increasing. A long a dream humans since beginning time but also to live good physical mental condition. Nutrition research focused on recent decades more food combination patterns than individual foods/nutrients due possible synergistic/antagonistic effects components dietary model. Various have been associated with health benefits, largest body evidence literature attributable traditional habits lifestyle followed by populations from Mediterranean region. After Seven Countries Study, many prospective observational studies trials diverse reinforced beneficial higher adherence diet reference prevention/management age-associated non-communicable diseases, such as cardiovascular metabolic neurodegenerative cancer, depression, respiratory fragility fractures. In addition, ecologically sustainable. Therefore, this immaterial heritage constitutes healthy way eating living respecting environment.

Language: Английский

Citations

230