TY - JOUR
T1 - Human apolipoprotein C-I expression in mice impairs learning and memory functions
AU - Abildayeva, K.
AU - Berbee, J.F.
AU - Blokland, A.
AU - Jansen, P.J.
AU - Hoek, F.
AU - Meijer, O.
AU - Lutjohann, D.
AU - Gautier, T.
AU - Pillot, T.
AU - de Vente, J.
AU - Havekes, L.M.
AU - Ramaekers, F.C.S.
AU - Kuipers, F.
AU - Rensen, P.C.
AU - Mulder, M.T.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - 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.
AB - 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.
U2 - 10.1194/jlr.M700518-JLR200
DO - 10.1194/jlr.M700518-JLR200
M3 - Article
C2 - 18160739
SN - 0022-2275
VL - 49
SP - 856
EP - 869
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 4
ER -