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

K. Abildayeva, J.F. Berbee, A. Blokland, P.J. Jansen, F. Hoek, O. Meijer, D. Lutjohann, T. Gautier, T. Pillot, J. de Vente, L.M. Havekes, F.C.S. Ramaekers, F. Kuipers, P.C. Rensen, M.T. Mulder

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The H2 allele of APOC I, 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 R-amyloid (A beta) in plaques in AD brains, and in vitro experiments revealed that aggregation of A beta was delayed in the presence of apoC-I. Moreover, apoC-I was found to exacerbate the soluble A beta 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 transgenic and wild-type mice. In conclusion, human apoC-I expression impairs cognitive functions in mice independent of apoE expression, which supports the potential of a modulatory role for apoC-I during the development of AD.
Original languageEnglish
Pages (from-to)856-869
JournalJournal of Lipid Research
Volume49
Issue number4
DOIs
Publication statusPublished - 1 Jan 2008

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