A beta 42 neurotoxicity in primary co-cultures: Effect of apoE isoform and A beta conformation

• Published in: Neurobiology of aging 2007-08, Vol.28 (8), p.1139-1147
• Main Authors: Manelli, Arlene M, Bulfinch, Lindsey C, Sullivan, Patrick M, LaDu, Mary Jo
• Format: Article
• Language: English
• ISSN: 0197-4580
• DOI: 10.1016/j.neurobiolaging.2006.05.024

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 [var 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 42-induced neurotoxicity. These in vitro data demonstrate a gain of negative function for apoE4, synergistic with oligomeric A beta 42, in mediating neurotoxicity.