Dataset Information

ApoE-fragment/Aβ heteromers in the brain of patients with Alzheimer's disease.

ABSTRACT: Identification of endogenous pathological amyloid β peptides (Aβ) forms in the brains of patients with Alzheimer's disease (AD) is still unclear. In healthy brain, Aβ can associate with Apolipoprotein E (ApoE) which is involved in its metabolism and clearance. In the brain of patients with AD, ApoE is cleaved and produces ApoE fragments. We studied the forms of Aβ and their interaction with the ApoE fragments in post-mortem brains from control and AD patients by western blots and co-immunoprecipitation. Three Aβ-containing peptides and three ApoE fragments were specifically found in the brain of AD patients. Co-immunoprecipitations showed that ApoE fragments and Aβ1-42 peptides are co-partners in heteromers of 18 and 16 kDa while ApoE-fragments and Aβ peptides of 12 kDa did not interact with each other. Formation of the 18 kDa ApoE-fragment/Aβ heteromers is specifically increased in ApoE4 carriers and is a strong brain marker of AD while 16 kDa ApoE-fragment/Aβ and Aβ 12 kDa correlate to memory deficit. These data show that in patients with AD, ApoE fragmentation generates peptides that trap Aβ in the brain. Inhibiting the fragmentation or targeting ApoE fragments could be exploited to define strategies to detect or reverse AD.

SUBMITTER: Mouchard A

PROVIDER: S-EPMC6408522 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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ApoE-fragment/Aβ heteromers in the brain of patients with Alzheimer's disease.

Mouchard Amandine A Boutonnet Marie-Charlotte MC Mazzocco Claire C Biendon Nathalie N Macrez Nathalie N

Scientific reports 20190308 1

Identification of endogenous pathological amyloid β peptides (Aβ) forms in the brains of patients with Alzheimer's disease (AD) is still unclear. In healthy brain, Aβ can associate with Apolipoprotein E (ApoE) which is involved in its metabolism and clearance. In the brain of patients with AD, ApoE is cleaved and produces ApoE fragments. We studied the forms of Aβ and their interaction with the ApoE fragments in post-mortem brains from control and AD patients by western blots and co-immunoprecip ...[more]

PMID: 30850702

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Project description:Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation. In this editorial review, we present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (TLR4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways, resulting in an adverse NIP that causes neuronal dysfunction. NIP, Neuroinflammatory phenotype; P.I., pro-inflammatory; A.I., anti-inflammatory.

Dataset Information

ApoE-fragment/Aβ heteromers in the brain of patients with Alzheimer's disease.

Publications

ApoE-fragment/Aβ heteromers in the brain of patients with Alzheimer's disease.

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