APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms.
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.
Litwin Zucker Center for the Study of Alzheimer's Disease, Feinstein Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.
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Conejero-Goldberg
1] Litwin Zucker Center for the Study of Alzheimer's Disease, Feinstein Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA [2] FIDMAG, Hermanas Hospitalarias, Sant Boi de Llobregat, Spain.
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JJ
Gomar
Litwin Zucker Center for the Study of Alzheimer's Disease, Feinstein Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.
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Bobes-Bascaran
Neuropathology Section, Lieber Institute for Brain Development, Baltimore, MD, USA.
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Hyde
Neuropathology Section, Lieber Institute for Brain Development, Baltimore, MD, USA.
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JE
Kleinman
Section on Neuropathology, Clinical Brain Disorders Branch, GCAPP, IRP, National Institute of Mental Health, NIH, Bethesda, MD, USA.
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Herman
Litwin Zucker Center for the Study of Alzheimer's Disease, Feinstein Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.
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Chen
Litwin Zucker Center for the Study of Alzheimer's Disease, Feinstein Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.
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Davies
Litwin Zucker Center for the Study of Alzheimer's Disease, Feinstein Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.
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Goldberg
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D053329:Apolipoprotein E2 / Q000235:genetics* / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002540:Cerebral Cortex / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000235:genetics / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012306:Risk
D053329:Apolipoprotein E2; D015415:Biomarkers; D016023:Integrins; D007797:Laminin; D020033:Protein Isoforms; D012333:RNA, Messenger; D003094:Collagen