Neuroinflammation in Alzheimer’s Disease

Biomedicines, Год журнала: 2021, Номер 9(5), С. 524 - 524

Опубликована: Май 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.

Язык: Английский

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Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress

Free Radical Biology and Medicine, Год журнала: 2022, Номер 193, С. 134 - 157

Опубликована: Окт. 4, 2022

Язык: Английский

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Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Июнь 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.

Язык: Английский

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Single-cell multiregion dissection of Alzheimer’s disease

Nature, Год журнала: 2024, Номер 632(8026), С. 858 - 868

Опубликована: Июль 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.

Язык: Английский

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Whole‐genome sequencing reveals new Alzheimer's disease–associated rare variants in loci related to synaptic function and neuronal development

Alzheimer s & Dementia, Год журнала: 2021, Номер 17(9), С. 1509 - 1527

Опубликована: Апрель 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.

Язык: Английский

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

Molecular Psychiatry, Год журнала: 2021, Номер 26(10), С. 6065 - 6073

Опубликована: Авг. 11, 2021

Язык: Английский

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Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems

Cellular and Molecular Life Sciences, Год журнала: 2021, Номер 78(23), С. 7397 - 7426

Опубликована: Окт. 27, 2021

Язык: Английский

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African ancestry GWAS of dementia in a large military cohort identifies significant risk loci

Molecular Psychiatry, Год журнала: 2022, Номер 28(3), С. 1293 - 1302

Опубликована: Дек. 22, 2022

Язык: Английский

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The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

Alzheimer s & Dementia, Год журнала: 2023, Номер 20(1), С. 652 - 694

Опубликована: Сен. 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.

Язык: Английский

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New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN

Physiological Reviews, Год журнала: 2023, Номер 104(1), С. 399 - 472

Опубликована: Авг. 24, 2023

Cell excitability and its modulation by hormones neurotransmitters involve the concerted action of a large repertoire membrane proteins, especially ion channels. Unique complements coexpressed channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that tailored for diverse physiological contributions, dysfunction any component may induce disease state. A crucial parameter controlling is resting potential (RMP) set extra- intracellular concentrations ions, mainly Na + , K Cl − their passive permeation across through leak Indeed, dysregulation RMP causes significant effects on cellular excitability. This review describes molecular channel NALCN, which associates with accessory subunits UNC-79, UNC-80, NLF-1/FAM155 to conduct depolarizing background currents various neurons. Studies animal models clearly demonstrate NALCN contributes fundamental processes nervous system including control respiratory rhythm, circadian sleep, locomotor behavior. Furthermore, associated severe pathological states humans. The critical involvement physiology now well established, but study has been hampered lack specific drugs can block or agonize vitro vivo. Molecular tools available accelerate our understanding how key functions development novel therapies channelopathies.

Язык: Английский

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