Title

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

24492349

DOI

10.1038/mp.2013.194