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

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 b-amyloid (Ab) in plaques in AD brains, and in vitro experiments revealed that aggregation of Ab 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 1/0 transgenic mice that express APOC1 mRNA throughout their brains and apoC-I protein in astrocytes and endothelial cells. The hAPOC1 1/0 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 5 0.012) and in the Morris water maze task (P 5 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

Relation between plasma and brain lipids

“…The most significant change due to aging is observed in gene expression levels of APOD [85]; CSF and hippocampal apoD levels are elevated in Alzheimer's disease [86] and correlated with disease severity [87]. ApoC-I colocalizes with amyloid-b plaques in human Alzheimer's disease brain [88], has been suggested to influence neuroinflammation in Alzheimer's disease [89], and may contribute to genetic susceptibility possibly via linkage disequilibrium with APOE e4 [89][90][91]. In Alzheimer's disease mice, Apoa4 deficiency increases amyloid-b load, enhances neuronal loss, accelerates cognitive dysfunction, and increases mortality [92].…”

What are lipoproteins doing in the brain?

“…Out of the three major isoforms of apoE – apoE2, apoE3, and apoE4, apoE4 confers the major risk for Alzheimer’s disease (AD). The expression of apoE4 allele usually results in increased expression of apoC1 22 Mice overexpressing human apoC1 also display impaired learning and memory 23 . Interestingly apoC1−/− mice also show impaired hippocampal-dependent memory with no gross changes in brain morphology or brain cholesterol levels, but increased expression of the proinflammatory marker tumor necrosis factor-α 24 .…”

Performance Metrics for Selecting Single Nucleotide Polymorphisms in Late-onset Alzheimer’s Disease

“…APOC1 is produced by astrocytes33 and regulates lipoprotein metabolism via its interaction with APOE 34 by masking or altering the conformation of APOE on lipoprotein particles35. In addition, an animal study showed that apoC-1 may affect cognitive functions by lowering the expression of apoE or offsetting the effects of apoE on lipid distribution in the brains of mice36.…”