Human apolipoprotein C-I expression in mice impairs learning and memory functions.
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.
Abildayeva
Karlygash
K
Department of Molecular Cell Biology and Department of Basic Neurosciences, European Graduate School of Neuroscience, Institute Brain and Behavior, University of Maastricht, Maastricht, The Netherlands.
Berbée
Jimmy F P
JF
Blokland
Arjan
A
Jansen
Paula J
PJ
Hoek
Frans J
FJ
Meijer
Onno
O
Lütjohann
Dieter
D
Gautier
Thomas
T
Pillot
Thierry
T
De Vente
Jan
J
Havekes
Louis M
LM
Ramaekers
Frans C S
FC
Kuipers
Folkert
F
Rensen
Patrick C N
PC
Mulder
Monique
M
D000818:Animals; D053302:Apolipoprotein C-I / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007858:Learning; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D046509:Tissue Culture Techniques
C505803:APOC1 protein, human; D053302:Apolipoprotein C-I; D012333:RNA, Messenger