Apolipoprotein E4 domain interaction induces endoplasmic reticulum stress and impairs astrocyte function.
Domain interaction, a structural property of apolipoprotein E4 (apoE4), is predicted to contribute to the association of apoE4 with Alzheimer disease. Arg-61 apoE mice, a gene-targeted mouse model specific for domain interaction, have lower brain apoE levels and synaptic, functional, and cognitive deficits. We hypothesized that domain interaction elicits an endoplasmic reticulum (ER) stress in astrocytes and an unfolded protein response that targets Arg-61 apoE for degradation. Primary Arg-61 apoE astrocytes had less intracellular apoE than wild-type astrocytes, and unfolded protein response markers OASIS (old astrocyte specifically induced substance), ATF4, and XBP-1 and downstream effectors were up-regulated. ER stress appears to cause global astrocyte dysfunction as glucose uptake was decreased in Arg-61 apoE astrocytes, and astrocyte-conditioned medium promoted neurite outgrowth less efficiently than wild-type medium in Neuro-2a cell cultures. We showed age-dependent up-regulation of brain OASIS levels and processing in Arg-61 apoE mice. ER stress and astrocyte dysfunction represent a new paradigm underlying the association of apoE4 with neurodegeneration.
Zhong
Ning
N
Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
Ramaswamy
Gayathri
G
Weisgraber
Karl H
KH
D000818:Animals; D053327:Apolipoprotein E4 / Q000737:chemistry* / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013312:Stress, Physiological; D015854:Up-Regulation
D053327:Apolipoprotein E4; C119923:Creb3l1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D001120:Arginine; D002784:Cholesterol; D005947:Glucose