APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms
Publication Date
2014
Journal Title
Mol Psychiatry
Abstract
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.
Volume Number
19
Issue Number
11
Pages
1243-1250
Document Type
Article
EPub Date
2014/02/05
Status
Faculty, Northwell Researcher, Northwell Resident
Facility
School of Medicine; Northwell Health
Primary Department
Psychiatry
Additional Departments
Molecular Medicine
PMID
DOI
10.1038/mp.2013.194