Abeta42 neurotoxicity in primary co-cultures: effect of apoE isoform and Abeta conformation.
Autosomal dominant mutations that increase amyloid-beta(1-42) (Abeta42) cause familial Alzheimer's disease (AD), and the most common genetic risk factor for AD is the presence of the epsilon4 allele of apolipoprotein E (apoE). Previously, we characterized stable preparations of Abeta42 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 Abeta42 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 Abeta42 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 Abeta42-induced neurotoxicity. These in vitro data demonstrate a gain of negative function for apoE4, synergistic with oligomeric Abeta42, in mediating neurotoxicity.
Manelli
Arlene M
AM
Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, United States.
Bulfinch
Lindsey C
LC
Sullivan
Patrick M
PM
LaDu
Mary Jo
MJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000737:chemistry / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D011247:Pregnancy; D011487:Protein Conformation; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D013997:Time Factors
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42); D000255:Adenosine Triphosphate