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

Publication Type:

Journal Article

Source:

J Lipid Res, Volume 49, Number 4, p.856-869 (2008)

DOI Name (links to online publication)

10.1194/jlr.M700518-JLR200

Keywords:

Affect; Alzheimer; '; s disease; apoE; Astrocytes; Behavior; Brain; CELL; CELLS; Development; Disease; EXPRESSION; GENE; Gene Expression; GENE-EXPRESSION; Human; In Vitro; IN-VITRO; Learning; Lipid Metabolism; Memory; metabolism; Mice; MORRIS WATER MAZE;

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 beta-amyloid (Abeta) in plaques in AD brains, and in vitro experiments revealed that aggregation of Abeta was delayed in the presence of apoC-I. Moreover, apoC-I was found to exacerbate the soluble Abeta 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

18/01/2013