Dataset Information

Apolipoprotein E4-driven effects on inflammatory and neurotrophic factors in peripheral extracellular vesicles from cognitively impaired, no dementia participants who converted to Alzheimer's disease.

ABSTRACT:

Introduction

In brain, extracellular vesicles (EVs) play an essential role in the neuron-glia interface and ensure the crosstalk between the brain and the periphery. Some studies now link the pathway dysfunction of the EVs to apolipoprotein E gene variant (APOE ?4) and the risk of progression to Alzheimer's disease (AD). To better understand the role of APOE ?4 in pre-clinical AD, we have determined levels of pathogenic, neurotrophic and inflammatory proteins in peripheral EVs (pEVs) and in plasma from cognitively impaired, no dementia (CIND) participants stratified upon the absence (APOE ?4^-) or the presence (APOE ?4⁺ ) of the ?4 allele of APOE.

Methods

Levels of 15 neurodegenerative, neurotrophic and neuroinflammatory proteins were quantified in pEVs and compared to their plasma levels from cognitively normal and CIND participants.

Results

Levels of neurotrophic and inflammatory markers were reduced in pEVs from APOE ?4⁺. The pentraxin-2/?-synuclein ratio measured in pEVs was able to predict AD 5 years before the onset among APOE ?4⁺-CIND individuals.

Discussion

Our findings suggest an alteration of the endosomal pathway in APOE ?4⁺ and that pEVs pentraxin-2/?-synuclein ratio could serve as a useful early biomarker for AD susceptibility.

SUBMITTER: Ben Khedher MR

PROVIDER: S-EPMC7842191 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Apolipoprotein E4-driven effects on inflammatory and neurotrophic factors in peripheral extracellular vesicles from cognitively impaired, no dementia participants who converted to Alzheimer's disease.

Ben Khedher Mohamed Raâfet MR Haddad Mohamed M Laurin Danielle D Ramassamy Charles C

Alzheimer's & dementia (New York, N. Y.) 20210128 1

<h4>Introduction</h4>In brain, extracellular vesicles (EVs) play an essential role in the neuron-glia interface and ensure the crosstalk between the brain and the periphery. Some studies now link the pathway dysfunction of the EVs to apolipoprotein E gene variant (<i>APOE</i> ε4) and the risk of progression to Alzheimer's disease (AD). To better understand the role of <i>APOE</i> ε4 in pre-clinical AD, we have determined levels of pathogenic, neurotrophic and inflammatory proteins in peripheral ...[more]

PMID: 33537405

Similar Datasets

Project description:In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ?4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-? and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ?3 allele we show that the ?4 allele, whether homozygous or heterozygous with an ?3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-? precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.

Dataset Information

Apolipoprotein E4-driven effects on inflammatory and neurotrophic factors in peripheral extracellular vesicles from cognitively impaired, no dementia participants who converted to Alzheimer's disease.

Introduction

Methods

Results

Discussion

Publications

Apolipoprotein E4-driven effects on inflammatory and neurotrophic factors in peripheral extracellular vesicles from cognitively impaired, no dementia participants who converted to Alzheimer's disease.

Similar Datasets

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