Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model DOI Creative Commons
Gema Lordén, Jacob M. Wozniak, Kim Doré

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 23, 2022

Abstract Exquisitely tuned activity of protein kinase C (PKC) isozymes is essential to maintaining cellular homeostasis. Whereas loss-of-function mutations are generally associated with cancer, gain-of-function variants in one isozyme, PKCα, Alzheimer’s disease (AD). Here we show that the enhanced variant, PKCα M489V, sufficient rewire brain phosphoproteome, drive synaptic degeneration, and impair cognition a mouse model. This variant causes modest 30% increase catalytic without altering on/off activation dynamics or stability, underscoring biochemical, cellular, ultimately cognitive effects observed. Analysis hippocampal neurons from M489V mice reveals amyloid-β-induced depression reduced spine density compared wild-type mice. Behavioral studies reveal this mutation alone cognition, and, when coupled model AD, further accelerates decline. The druggability kinases positions as promising therapeutic target AD.

Language: Английский

Neuroinflammation in Alzheimer’s Disease DOI Creative Commons
Isaac G. Onyango, Gretsen Velezmoro Jáuregui, Mária Čarná

et al.

Biomedicines, Journal Year: 2021, Volume and Issue: 9(5), P. 524 - 524

Published: May 7, 2021

Alzheimer's disease (AD) is a neurodegenerative associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise increasing age. There are currently no effective modifying treatments for AD, resulting in increasingly large socioeconomic personal costs. Increasing age an increase low-grade chronic inflammation (inflammaging) that may contribute the process AD. Although exact mechanisms remain unclear, aberrant elevation reactive oxygen nitrogen species (RONS) levels from several endogenous exogenous processes brain not only affect cell signaling, but also trigger cellular senescence, inflammation, pyroptosis. Moreover, compromised immune privilege allows infiltration peripheral cells infectious agents play role. Additionally, meta-inflammation as well gut microbiota dysbiosis drive neuroinflammatory process. Considering inflammatory/immune pathways dysregulated parallel cognitive dysfunction elucidating relationship between central nervous system facilitate development safe therapy We discuss some current ideas on inflammaging appear summarize details few immunomodulatory strategies being developed selectively target detrimental aspects neuroinflammation without affecting defense against pathogens tissue damage.

Language: Английский

Citations

209
Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress DOI
Saikat Dewanjee, Pratik Chakraborty, Hiranmoy Bhattacharya

et al.

Free Radical Biology and Medicine, Journal Year: 2022, Volume and Issue: 193, P. 134 - 157

Published: Oct. 4, 2022

Language: Английский

Citations

129
Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials DOI Creative Commons
Jifei Miao,

Haixia Ma,

Yang Yang

et al.

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: June 15, 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregation in the brain. Recent studies have revealed critical role of microglia AD pathogenesis. This review provides comprehensive summary current understanding microglial involvement AD, focusing on genetic determinants, phenotypic state, phagocytic capacity, neuroinflammatory response, and impact synaptic plasticity neuronal regulation. Furthermore, recent developments drug discovery targeting are reviewed, highlighting potential avenues for therapeutic intervention. emphasizes essential insights into treatments.

Language: Английский

Citations

91
Single-cell multiregion dissection of Alzheimer’s disease DOI Creative Commons
Hansruedi Mathys, Carles A. Boix, Leyla Anne Akay

et al.

Nature, Journal Year: 2024, Volume and Issue: 632(8026), P. 858 - 868

Published: July 24, 2024

Abstract Alzheimer’s disease is the leading cause of dementia worldwide, but cellular pathways that underlie its pathological progression across brain regions remain poorly understood 1–3 . Here we report a single-cell transcriptomic atlas six different in aged human brain, covering 1.3 million cells from 283 post-mortem samples 48 individuals with and without disease. We identify 76 cell types, including region-specific subtypes astrocytes excitatory neurons an inhibitory interneuron population unique to thalamus distinct canonical subclasses. vulnerable populations are depleted specific disease, provide evidence Reelin signalling pathway involved modulating vulnerability these neurons. develop scalable method for discovering gene modules, which use cell-type-specific modules altered annotate differences associated diverse variables. astrocyte program cognitive resilience pathology, tying choline metabolism polyamine biosynthesis preserved function late life. Together, our study develops regional ageing provides insights into vulnerability, response pathology.

Language: Английский

Citations

62
Advances in Alzheimer's disease: A multifaceted review of potential therapies and diagnostic techniques for early detection DOI
Monika Sharma, Pankaj Pal, Sukesh Kumar Gupta

et al.

Neurochemistry International, Journal Year: 2024, Volume and Issue: 177, P. 105761 - 105761

Published: May 7, 2024

Language: Английский

Citations

16
Whole‐genome sequencing reveals new Alzheimer's disease–associated rare variants in loci related to synaptic function and neuronal development DOI
Dmitry Prokopenko, Sarah Morgan,

Kristina Mullin

et al.

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 17(9), P. 1509 - 1527

Published: April 2, 2021

Abstract Introduction Genome‐wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole‐genome sequencing (WGS) now permits genome‐wide analyses identify rare variants contributing AD risk. Methods We performed single‐variant and spatial clustering–based testing on (minor allele frequency [MAF] ≤1%) in a family‐based WGS‐based study of 2247 subjects from 605 multiplex families, followed by replication 1669 unrelated individuals. Results identified 13 new candidate that yielded consistent rare‐variant signals discovery cohorts (4 single‐variant, 9 spatial‐clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3 , CLSTN2 . Discussion Downstream novel highlight synaptic function, contrast common AD‐associated variants, which implicate innate immunity amyloid processing. These not been previously AD, emphasizing the ability WGS particularly outside exome.

Language: Английский

Citations

78
Identification of novel drug targets for Alzheimer’s disease by integrating genetics and proteomes from brain and blood DOI

Ya‐Nan Ou,

Yuxiang Yang,

Yue‐Ting Deng

et al.

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(10), P. 6065 - 6073

Published: Aug. 11, 2021

Language: Английский

Citations

71
Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems DOI
Yihan Li, Simon M. Laws, Luke A. Miles

et al.

Cellular and Molecular Life Sciences, Journal Year: 2021, Volume and Issue: 78(23), P. 7397 - 7426

Published: Oct. 27, 2021

Language: Английский

Citations

56
African ancestry GWAS of dementia in a large military cohort identifies significant risk loci DOI
Richard Sherva, Rui Zhang, Nathan Sahelijo

et al.

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(3), P. 1293 - 1302

Published: Dec. 22, 2022

Language: Английский

Citations

45
The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022 DOI Creative Commons
Dallas P. Veitch, Michael W. Weiner,

Melanie J. Miller

et al.

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(1), P. 652 - 694

Published: Sept. 12, 2023

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, biofluid samples. We used conventional search methods identify 1459 publications from 2021 2022 using data/samples reviewed 291 impactful studies. This review details how studies improved progression understanding trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, modeling trials plasma biomarkers like phosphorylated tau showed promise for use. Biomarkers amyloid beta, tau, neurodegeneration, inflammation, others were prognostic with individualized prediction algorithms available online. Studies supported the cascade, emphasized importance neuroinflammation, detailed widespread heterogeneity disease, linked genetic vascular risk, co-pathologies, sex, resilience. Biological subtypes consistently observed. Generalizability results is limited by lack cohort diversity, an issue ADNI-4 address enrolling a diverse cohort.

Language: Английский

Citations

36