Human apolipoprotein C-I expression in mice impairs learning and memory functions
article
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 Ab 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 transgenie and wild-type mice. Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
Topics
Physiological Sciencesβ-amyloidAlzheimer's diseaseApolipoprotein EMorris water maze taskObject recognition taskamyloid beta proteinapolipoprotein Ecampesterolcholestanolcholesterolcholesterol derivativedesmosterollanosterollathosterollysophosphatidylcholinelysophosphatidylethanolaminemessenger RNAphosphatidylcholinephosphatidylethanolaminephosphatidylinositolphosphatidylserinesitosterolsphingomyelinunclassified druganimal cellanimal experimentanimal modelanimal tissueapoptosisastrocytebrain levelcell viabilitycontrolled studydisease exacerbationendothelium cellfemalehippocampushuman tissuelearning disorderlipid metabolismmaze testmemory disordermousenerve cell necrosisnonhumanprotein aggregationprotein expressionrecognitiontask performancetransgenic mousewild typeanimalC57BL mousegene expression regulationgeneticsmetabolismAnimalsApolipoprotein C-IGene Expression RegulationHumansImmunohistochemistryLearningMemoryMiceMice, Inbred C57BLMice, TransgenicRNA, MessengerTissue Culture Techniques
TNO Identifier
240744
ISSN
00222275
Source
Journal of Lipid Research, 49(4), pp. 856-869.
Pages
856-869