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Journal of Lipid Research, Vol. 49, 856-869, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Human apolipoprotein C-I 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^1,*

^* Department of Molecular Cell Biology and Department of Basic Neurosciences, European Graduate School of Neuroscience, Institute Brain and Behavior, University of Maastricht, Maastricht
^** Faculty of Psychology, Institute Brain and Behavior, University of Maastricht, Maastricht
Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, TNO-Quality of Life, Gaubius Laboratory, Leiden
Department of Biomedical Research, TNO-Quality of Life, Gaubius Laboratory, Leiden
Department of Clinical Chemistry, Academic Medical Center, Amsterdam
Department of Medical Pharmacology, Leiden Amsterdam Center for Drug Research and Leiden Medical Center, Leiden
Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
^*** Department of Clinical Pharmacology, University of Bonn, Bonn, Germany
Laboratoire de Médecine et Thérapeutique Moléculaire, Lipidomix, Institut National Polytechnique de Lorraine, Nancy, France

Published, JLR Papers in Press, December 26, 2007.

¹ To whom correspondence should be addressed. e-mail: m.mulder{at}np.unimaas.nl

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 Aβ 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 littermates, 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.

Supplementary key words Alzheimer's disease • apolipoprotein E • object recognition task • Morris water maze task • β-amyloid