Human apolipoprotein CI expression in mice impairs learning and memory functions

Karlygash Abildayeva, Jimmy F. P. Berbée, Arjan Blokland, Paula J. Jansen, Frans J. Hoek, Onno Meijer, Dieter Lütjohann, Thomas Gautier, Thierry Pillot, Jan De Vente, Louis M. Havekes, Frans C. S. Ramaekers, Folkert Kuipers, Patrick C. N. Rensen, and Monique Mulder

Department of Neuroscience, University of Maastricht, Maastricht 6200MD

Corresponding Author: M.Mulder{at}NP.unimaas.nl

The H2 allele of APOC1, giving rise to increased gene expression of apolipoprotein CI (apoCI), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoCI protein is present in astrocytes and endothelial cells within hippocampal regions, in both human control and AD brains. Interestingly, apoCI co-localized with ß-amyloid (Aß) in plaques in AD brains and in vitro experiments revealed that aggregation of Aß is delayed in the presence of apoCI. Moreover, apoCI was found to exacerbate the soluble Aß oligomer-induced neuronal death. In order to establish a potential role for apoCI in cognitive functions we used human APOC1+/0 transgenic mice that express APOC1 mRNA throughout their brains and apoCI protein in astrocytes and endothelial cells. The hAPOC1+/0 mice display impaired hippocampal-dependent learning and memory functions compared to their wild-type littermates as judged from their performance in the object recognition task (P=0.012) and in the Morris water maze task (P=0.010). ApoCI may affect learning due to its inhibitory properties towards 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 apoCI expression impairs cognitive functions in mice independent of apoE expression, which supports the potential of a modulatory role for apoCI during the development of AD.

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