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APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms
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APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms
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Journal Article
APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms
2014
Overview
The common APOE2 gene variant is neuroprotective against Alzheimer’s disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins.
In vivo
studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 692/53
/ Adult
/ Aged
/ Alzheimer Disease - diagnosis
/ Alzheimer Disease - genetics
/ Alzheimer Disease - physiopathology
/ Apolipoprotein E2 - genetics
/ Apolipoprotein E2 - metabolism
/ Brain
/ Cerebral Cortex - physiopathology
/ Cognitive Dysfunction - genetics
/ Cognitive Dysfunction - physiopathology
/ Collagen
/ Disease
/ Extracellular Matrix - metabolism
/ Female
/ Humans
/ Long-Term Potentiation - physiology
/ Male
/ Medicine
/ Protein Isoforms - metabolism
/ Proteins
/ Risk
