CSF complement proteins are elevated in prodromal to moderate Alzheimer's disease patients and are not altered by the anti‐tau antibody semorinemab DOI Creative Commons

Cosme Sandoval,

Julie Lee, Balázs István Tóth

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(11), P. 7940 - 7953

Published: Oct. 6, 2024

Abstract INTRODUCTION Growing evidence suggests a role for neuroinflammation in Alzheimer's disease (AD). We investigated complement pathway activity AD patient cerebrospinal fluid (CSF) and evaluated its modulation by the anti‐tau antibody semorinemab. METHODS Immunoassays were applied to measure CSF proteins C4, factor B (FB), C3 their cleavage fragments C4a, C3a, Bb (Bb) patients separate cognitively unimpaired (CU) cohort. RESULTS All measured increased versus CU subjects, with C4a displaying most robust increase. Finally, semorinemab did not have significant pharmacodynamic effect on proteins. DISCUSSION Elevated levels of C3, Bb, FB are consistent activation brains. Despite showing reduction soluble tau species, impact protein or activity. Further studies needed determine value as biomarkers AD. Highlights Cerebrospinal (AD) compared Baseline correlated neuro‐axonal degeneration glial patients. The investigational relative placebo arm.

Language: Английский

Inflammatory aspects of Alzheimer’s disease DOI
Pablo Botella Lucena, Michael T. Heneka

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Aug. 28, 2024

Language: Английский

Citations

27
Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease DOI Creative Commons

Vanesa R. Hyde,

Chaoming Zhou,

J R Muñóz y Fernández

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: unknown, P. 115109 - 115109

Published: Jan. 1, 2025

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies infectious agents, with herpes simplex virus 1 (HSV-1) being leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression herpesvirus protein ICP27 increases severity strongly colocalizes p-tau but not Aβ. Modeling organoids shows that HSV-1 infection elevates phosphorylation. Notably, reduces expression markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB IRF-3, which AD. Furthermore, experimental activation STING enhances phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest phosphorylation acts as an innate immune response AD, driven by cGAS-STING.

Language: Английский

Citations

10
Clonal hematopoiesis, somatic mosaicism, and age-associated disease DOI
Megan A. Evans, Kenneth Walsh

Physiological Reviews, Journal Year: 2022, Volume and Issue: 103(1), P. 649 - 716

Published: Sept. 1, 2022

Somatic mosaicism, the occurrence of multiple genetically distinct cell clones within same tissue, is an evitable consequence human aging. The hematopoietic system no exception to this, where studies have revealed presence expanded blood carrying mutations in preleukemic driver genes and/or genetic alterations chromosomes. This phenomenon referred as clonal hematopoiesis and remarkably prevalent elderly individuals. While represents early step toward a hematological malignancy, most individuals will never develop cancer. Somewhat unexpectedly, epidemiological found that associated with increase risk all-cause mortality age-related disease, particularly cardiovascular system. Studies using murine models begun shed light on this relationship, suggesting mature cells can causally contribute aging disease by augmenting inflammatory processes. Here we provide up-to-date review context somatic mosaicism describe recent reported associations disease. We also discuss experimental provided important mechanistic insight into how promote knowledge could be leveraged treat hematopoiesis.

Language: Английский

Citations

52
Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease DOI Creative Commons
Carlos Cruchaga, Daniel Western, Jigyasha Timsina

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: June 9, 2023

The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes disease-associated loci. QTL mapping mainly been focused on multi-tissue expression or plasma protein (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs which 1,585 are unique to CSF, demonstrating genetic regulation CSF proteome. In addition established chr6p22.2-21.32 HLA region, pleiotropic regions chr3q28 near

Language: Английский

Citations

26
Associations of infections and vaccines with Alzheimer's disease point to a role of compromised immunity rather than specific pathogen in AD DOI Creative Commons
Svetlana Ukraintseva, Arseniy Yashkin, Igor Akushevich

et al.

Experimental Gerontology, Journal Year: 2024, Volume and Issue: 190, P. 112411 - 112411

Published: April 2, 2024

Diverse pathogens (viral, bacterial, fungal) have been associated with Alzheimer's disease (AD) and related traits in various studies. This suggests that compromised immunity, rather than specific microbes, may play a role AD by increasing an individual's vulnerability to infections, which could contribute neurodegeneration. If true, then vaccines heterologous effects on extending beyond protection against the targeted disease, hold potential for prevention.

Language: Английский

Citations

13
Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease DOI
Daniel Western, Jigyasha Timsina,

Lihua Wang

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(12), P. 2672 - 2684

Published: Nov. 11, 2024

Language: Английский

Citations

9
The Vascular-Immune Hypothesis of Alzheimer’s Disease DOI Creative Commons
Rashi I. Mehta, Rupal I. Mehta

Biomedicines, Journal Year: 2023, Volume and Issue: 11(2), P. 408 - 408

Published: Jan. 30, 2023

Alzheimer’s disease (AD) is a devastating and irreversible neurodegenerative disorder with unknown etiology. While its cause unclear, number of theories have been proposed to explain the pathogenesis AD. In large part, these centered around potential causes for intracerebral accumulation beta-amyloid (βA) tau aggregates. Yet, persons AD dementia often exhibit autopsy evidence mixed brain pathologies including myriad vascular changes, injuries, complex inflammation, protein inclusions in addition hallmark neuropathologic lesions AD, namely insoluble βA plaques neurofibrillary tangles (NFTs). Epidemiological data demonstrate that overlapping diminish plaque NFT threshold necessary precipitate clinical dementia. Moreover, subset who pathology remain resilient while other clinically-defined do not AD-defining lesions. It increasingly recognized pathologically heterogeneous biologically multifactorial uncharacterized biologic phenomena involved genesis progression. Here, we review literature regard criteria incipient discuss converging concepts regarding immune factors

Language: Английский

Citations

22
Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer’s disease DOI Creative Commons
L. Meng, Han Jin,

Burak Yuluğ

et al.

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Oct. 2, 2024

Language: Английский

Citations

8
Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification DOI Creative Commons
Huan Zhong, Xiaopu Zhou,

Hyebin Uhm

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(4), P. 2469 - 2484

Published: Feb. 7, 2024

Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells.

Language: Английский

Citations

7
“Brain‐IT”: Exergame training with biofeedback breathing in neurocognitive disorders DOI Creative Commons
Patrick Manser, Eling D. de Bruin

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(7), P. 4747 - 4764

Published: May 29, 2024

The combination of exergame-based motor-cognitive training with resonance breathing guided by heart-rate variability biofeedback (HRV-BF) targets various relevant mechanisms action to alleviate the pathological state in mild neurocognitive disorders (mNCD).

Language: Английский

Citations

7