Aβ42 neurotoxicity in primary co-cultures:: Effect of apoE isoform and Aβ conformation

NEUROBIOLOGY OF AGING

卷:28

Article

Manelli, Arlene M. ; Bulfinch, Lindsey C. ; Sullivan, Patrick M. ; LaDu, Mary Jo

关键词: ApoE;    Alzheimer disease;    amyloid-beta;    neurotoxicity;    co-cultures;    ApoE transgenic mice;   

DOI  :  10.1016/j.neurobiolaging.2006.05.024

来源: Elsevier

【 摘 要 】

Autosomal dominant mutations that increase amyloid-beta(1-42) (A beta 42) cause familial Alzheimer's disease (AD), and the most common genetic risk factor for AD is the presence of the epsilon 4 allele of apolipoprotein E (apoE). Previously, we characterized stable preparations of A beta 42 oligomers and fibrils and reported that oligomers induced a 10-fold greater increase in neurotoxicity than fibrils in Neuro-2A cells. To determine the effects of apoE genotype on A beta 42 oligomer- and fibril-induced neurotoxicity in vitro, we co-cultured wild type (WT) neurons with glia from WT, apoE-knockout (apoE-KO), and human apoE2-, E3-, and E4-targeted replacement (TR) mice. Dose-dependent neurotoxicity was induced by oligomeric A beta 42 with a ranking order of apoE4-TR > KO = apoE2-TR = apoE3-TR > WT. Neurotoxicity induced by staurosporine or glutamate were not affected by apoE genotype, indicating specificity for oligomeric A beta 42induced neurotoxicity. These in vitro data demonstrate a gain of negative function for apoE4, synergistic with oligomeric A beta 42, in mediating neurotoxicity. (c) 2006 Elsevier Inc. All rights reserved.

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