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Human apolipoprotein C-I expression in mice impairs learning and memory functions

Author: Abildayeva, K. · Berbée, J.F.P. · Blokland, A. · Jansen, P.J. · Hoek, F.J. · Meijer, O. · Lütjohann, D. · Gautier, T. · Pillot, T. · Vente, J.de · Havekes, L.M. · Ramaekers, F.C.S. · Kuipers, F. · Rensen, P.C.N. · Mulder, M.
Type:article
Date:2008
Institution: TNO Kwaliteit van Leven
Source:Journal of Lipid Research, 4, 49, 856-869
Identifier: 240744
doi: doi:10.1194/jlr.M700518-JLR200
Keywords: Health · Physiological Sciences · β-amyloid · Alzheimer's disease · Apolipoprotein E · Morris water maze task · Object recognition task · amyloid beta protein · apolipoprotein E · campesterol · cholestanol · cholesterol · cholesterol derivative · desmosterol · lanosterol · lathosterol · lysophosphatidylcholine · lysophosphatidylethanolamine · messenger RNA · phosphatidylcholine · phosphatidylethanolamine · phosphatidylinositol · phosphatidylserine · sitosterol · sphingomyelin · unclassified drug · animal cell · animal experiment · animal model · animal tissue · apoptosis · astrocyte · brain level · cell viability · controlled study · disease exacerbation · endothelium cell · female · hippocampus · human tissue · learning disorder · lipid metabolism · maze test · memory disorder · mouse · nerve cell necrosis · nonhuman · protein aggregation · protein expression · recognition · task performance · transgenic mouse · wild type · animal · C57BL mouse · gene expression regulation · genetics · metabolism · Animals · Apolipoprotein C-I · Gene Expression Regulation · Humans · Immunohistochemistry · Learning · Memory · Mice · Mice, Inbred C57BL · Mice, Transgenic · RNA, Messenger · Tissue Culture Techniques

Abstract

The H2 allele of APOC1, giving rise to increased gene expression of apolipoprotein C-I (apoC-I), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoC-I protein is present in astrocytes and endothelial cells within hippocampal regions in both human control and AD brains. Interestingly, apoC-I colocalized with β-amyloid (Aβ) in plaques in AD brains, and in vitro experiments revealed that aggregation of Aβ was delayed in the presence of apoC-I. Moreover, apoC-I was found to exacerbate the soluble Ab oligomer-induced neuronal death. To establish a potential role for apoC-I in cognitive functions, we used human (h) APOC1+/0 transgenic mice that express APOC1 mRNA throughout their brains and apoC-I protein in astrocytes and endothelial cells. The hAPOC1+/0 mice displayed impaired hippocampal-dependent learning and memory functions compared with their wild-type litter- mates, as judged from their performance in the object recognition task (P = 0.012) and in the Morris water maze task (P = 0.010). ApoC-I may affect learning as a result of its inhibitory properties toward apoE-dependent lipid metabolism. However, no differences in brain mRNA or protein levels of endogenous apoE were detected between transgenie and wild-type mice. Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.