Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 1979 - 1988

Published: Aug. 1, 2023

Abstract Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation amyloid-β (Aβ) peptide into plaques and microtubule protein tau neurofibrillary tangles (NFTs)—are hallmarks disease. However, other brain processes are thought to be key mediators Aβ plaque NFT pathology. How these additional pathologies evolve over course is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked coexpression can used characterize evolution a timescale spanning six decades. SMOC1 SPON1 proteins associated with were elevated CSF nearly 30 symptoms, followed by changes synaptic proteins, metabolic axonal inflammatory finally decreases neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers symptom as well or better than measures. Our results highlight multifaceted landscape pathophysiology its temporal evolution. Such knowledge will critical for developing precision therapeutic interventions biomarkers beyond those tau.

Language: Английский

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The potential of blood neurofilament light as a marker of neurodegeneration for Alzheimer's disease

Brain, Journal Year: 2023, Volume and Issue: 147(1), P. 12 - 25

Published: Aug. 2, 2023

Over the past several years, there has been a surge in blood biomarker studies examining value of plasma or serum neurofilament light (NfL) as neurodegeneration for Alzheimer's disease. However, have limited efforts to combine existing findings assess utility NfL In addition, we still need better insight into specific aspects that are reflected by elevated concentration NfL. this review, survey literature on cross-sectional and longitudinal relationships between blood-based levels other, neuroimaging-based, indices individuals continuum. Then, based classification established FDA-NIH Biomarker Working group, determine marker monitoring disease status (i.e. biomarker) predicting severity older adults with without cognitive decline prognostic risk/susceptibility biomarker). The current suggest exhibits great promise because an increased level appears reflect atrophy, hypometabolism white matter integrity, particularly brain regions typically affected Longitudinal evidence indicates can be useful not only progression patients but also susceptibility/risk likelihood abnormal alterations structure function cognitively unimpaired higher risk developing (e.g. those amyloid-β). There limitations research, discussed review. Nevertheless, extant strongly suggests serve valuable susceptibility disease-related clinical settings, well research settings.

Language: Английский

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Human Alzheimer’s disease reactive astrocytes exhibit a loss of homeostastic gene expression

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: Aug. 2, 2023

Astrocytes are one of the brain's major cell types and responsible for maintaining neuronal homeostasis via regulating extracellular environment, providing metabolic support, modulating synaptic activity. In neurodegenerative diseases, such as Alzheimer's disease, astrocytes can take on a hypertrophic appearance. These reactive canonically associated with increases in cytoskeletal proteins, glial fibrillary acidic protein vimentin. However, molecular alterations that characterize human disease tissues have not been extensively studied single resolution. Using nucleus RNA sequencing data from normal, pathologic aging, brains, we identified transcriptomic changes astrocytes. Deep learning-based clustering algorithms denoised expression 17,012 genes clustered 15,529 astrocyte nuclei, identifying protoplasmic, gray matter fibrous, white clusters. trajectory analyses revealed spectrum reactivity within protoplasmic characterized by modest increase marked decrease homeostatic genes. Amyloid but tau pathology correlated reactivity. To identify reactivity-associated genes, linear regressions gene versus were used to top 52 upregulated 144 downregulated Gene Ontology analysis cellular growth, responses metal ions, inflammation, proteostasis. Downregulated involved interactions, development, ERBB signaling, synapse regulation. Transcription factors significantly enriched among co-immunofluorescence staining brain tissues, confirmed downregulation ERBB4 transcription factor NFIA Our findings reveal exist is strong loss normal function.

Language: Английский

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Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 511 - 511

Published: March 14, 2024

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s (PD), traumatic brain injury (TBI) Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions these pathogeneses is currently not clearly understood. These show dysregulated inflammatory responses, activation neurons, glial cells, neurovascular unit damage associated with excessive release proinflammatory cytokines, chemokines, neurotoxic mediators, infiltration peripheral immune cells into brain, as well entry mediators through damaged endothelial blood–brain barrier tight junction proteins. Activation leads to many molecules that cause neuroinflammation neurodegeneration. Gulf War Illness (GWI) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) also dysfunctions. Currently, there no effective disease-modifying therapeutic options available for diseases. Human induced pluripotent stem cell (iPSC)-derived astrocytes, microglia, pericytes used models drug discovery. This review highlights certain recent trends in neuroinflammatory responses iPSC-derived applications

Language: Английский

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sc2GWAS: a comprehensive platform linking single cell and GWAS traits of human

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 53(D1), P. D1151 - D1161

Published: Nov. 20, 2024

Abstract Identifying cell populations associated with risk variants is essential for uncovering cell-specific mechanisms that drive disease development and progression. Integrating genome-wide association studies (GWAS) single-cell RNA sequencing (scRNA-seq) has become an effective strategy detecting trait–cell relationships. The accumulation of trait-related single data led to urgent need its comprehensively processing. To address this, we developed sc2GWAS (https://bio.liclab.net/sc2GWAS/), which aims document large-scale GWAS regulatory pairs at resolution provide comprehensive annotations enrichment analyses these related pairs. current version curates a total 15 078 310 candidate from > 6 300 000 individual cells, offering valuable resource exploring complex relationships between traits cells. We applied strict quality control measures on both scRNA-seq data, ensuring the reliability accuracy datasets identification trait-relevant cells genes. In addition, provides ranked lists genes extensive (epi) genetic annotations, making it downstream analyses. demonstrate utility platform by investigating Alzheimer’s disease, where identified significant associations microglial APOE gene emerging as particularly significant. This facilitates detailed research into trait–gene interactions, anticipate will mechanisms.

Language: Английский

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Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 18, 2025

Abstract Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player various neurodegenerative diseases brain disorders. Elevated CHI3L1 levels have been observed neurological conditions such traumatic injury (TBI), Alzheimer’s disease (AD), Parkinson’s (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob (CJD), multiple (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), tumors. This review explores the role of pathogenesis these disorders, with focus on its contributions to neuroinflammation, immune cell infiltration, neuronal degeneration. As regulator modulates microglia astrocyte activity, driving release proinflammatory cytokines that exacerbate progression. In addition pathology, promising biomarker for diagnosis monitoring cerebrospinal fluid (CSF) linked severity cognitive decline, particularly AD MS, highlighting potential clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, small-molecule inhibitors neutralizing antibodies, shown promise preclinical studies, demonstrating reduced amyloid plaque accumulation, improved survival. Despite potential, challenges remain developing selective safe CHI3L1-targeted therapies, ensuring effective delivery across blood–brain barrier mitigating off-target effects. addresses complexities highlights precision medicine, outlines future research directions aimed at unlocking full treating pathologies.

Language: Английский

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Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer's disease

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 0(0), P. 0 - 0

Published: Jan. 1, 2023

Blood-brain barrier disruption occurs in the early stages of Alzheimer's disease. Recent studies indicate a link between blood-brain dysfunction and cognitive decline might accelerate disease progression. Astrocytes are most abundant glial cells central nervous system with important roles structural functional maintenance barrier. For example, astrocytic coverage around endothelial perivascular endfeet secretion homeostatic soluble factors two major underlying mechanisms physiological functions. Astrocyte activation is often observed patients, astrocytes expressing high level fibrillary acid protein detected amyloid-beta plaque elevated phagocytic ability for amyloid-beta. Structural alterations including swollen endfeet, somata shrinkage possess loss contribute to vascular integrity at capillary arterioles levels. In addition, skewed into proinflammatory oxidative profiles increased secretions vasoactive mediators inducing junction immune cell infiltration. this review, we summarize findings existing literature on relevance astrocyte alteration response amyloid pathology context dysfunction. First, briefly describe maintenance. Then, review clinical evidence patients preclinical animal cellular models. We further discuss changes that correlates astrocyte. Finally, evaluate secreted by astrocytes, providing potential molecular modulation. conclude perspective investigating therapeutic targeting protection

Language: Английский

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Astrocytic Chitinase‐3‐like protein 1 in neurological diseases: Potential roles and future perspectives

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 165(6), P. 772 - 790

Published: April 7, 2023

Abstract Chitinase‐3‐like protein 1 (CHI3L1) is a secreted glycoprotein characterized by its ability to regulate multiple biological processes, such as the inflammatory response and gene transcriptional signaling activation. Abnormal CHI3L1 expression has been associated with neurological disorders serves biomarker for early detection of several neurodegenerative diseases. Aberrant also reportedly brain tumor migration metastasis, well contributions immune escape, playing important roles in progression. synthesized mainly reactive astrocytes central nervous system. Thus, targeting astrocytic could be promising approach treatment diseases, traumatic injury, ischemic stroke, Alzheimer's disease, Parkinson's sclerosis, amyotrophic lateral glioma. Based on current knowledge CHI3L1, we assume that it acts molecule mediating pathways driving initiation progression disorders. This narrative review first introduce potential We equally explore mRNA under physiological pathological conditions. Inhibiting disrupting interaction receptors through mechanisms action are briefly discussed. These endeavors highlight pivotal contribute development effective inhibitors based strategy structure‐based drug discovery, which an attractive therapeutic disease treatment. image

Language: Английский

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CHI3L1 signaling impairs hippocampal neurogenesis and cognitive function in autoimmune-mediated neuroinflammation

Science Advances, Journal Year: 2023, Volume and Issue: 9(39)

Published: Sept. 27, 2023

Chitinase-3–like protein 1 (CHI3L1) is primarily secreted by activated astrocytes in the brain and known as a reliable biomarker for inflammatory central nervous system (CNS) conditions such neurodegeneration autoimmune disorders like neuromyelitis optica (NMO). NMO an astrocyte disease caused autoantibodies targeting astroglial aquaporin 4 (AQP4) leads to vision loss, motor deficits, cognitive decline. In this study examining CHI3L1’s biological function neuroinflammation, we found that CHI3L1 expression correlates with impairment our patient cohort. Activated secrete response AQP4 autoantibodies, inhibits proliferation neuronal differentiation of neural stem cells. Mouse models showed decreased hippocampal neurogenesis impaired learning behaviors, which could be rescued depleting astrocytes. The molecular mechanism involves engaging CRTH2 receptor dampening β-catenin signaling neurogenesis. Blocking CHI3L1/CRTH2/β-catenin cascade restores improves suggesting potential therapeutic development neuroinflammatory disorders.

Language: Английский

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A critical appraisal of blood-based biomarkers for Alzheimer’s disease

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102290 - 102290

Published: April 1, 2024

Language: Английский

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