Apolipoprotein CI knock-out mice display impaired memory functions

J.F. Berbee, T. Vanmierlo, K. Abildayeva, A. Blokland, P.J. Jansen, D. Lütjohann, T. Gautier, E. Sijbrands, J. Prickaerts, M.h. Hadfoune, F.C.S. Ramaekers, F. Kuipers, P.C. Rensen, M. Mulder

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The epsilon 4 allele of apolipoprotein E (APOE4), which is a well established genetic risk factor for development of Alzheimer's disease (AD), is in genetic disequilibrium with the H2 allele of apolipoprotein C1 (APOC1), giving rise to increased expression of apoC-I. This raises the possibility that the H2 allele of APOC1, either alone or in combination with APOE4, provides a major risk factor for AD. In line herewith, we previously showed that mice overexpressing human APOC1 display impaired learning and memory functions. Here, we tested the hypothesis that the absence of Apoc1 expression in mice may improve memory functions. In contrast with our expectations, Apoc1(-/-) mice showed impaired hippocampal-dependent memory functions, as judged from their performance in the object recognition task (p <0.001) as compared to their wild-type littermates. No gross changes in brain morphology or in brain sterol concentrations were detected in knockout mice compared to wild-type littermates. Apoc1 deficiency reduced the expression of ApoE mRNA (-25%, p <0.05), but not ApoE protein levels. In line with a role for apoC-I in inflammatory processes, we observed significantly increased mRNA concentrations of the proinflammatory marker tumor necrosis factor alpha and oxidative stress related heme oxygenase 1 (Hmox1) in the absence of glial activation. In conclusion, the absence of ApoC-I results in impaired memory functions, which is, together with previous data, suggestive of an important, bell-shaped gene-dose dependent role for ApoC-I in appropriate brain functioning. The relative contributions of the H2 allele of APOC1 and/or APOE4 in the risk assessment in AD remain to be determined.

Original languageEnglish
Pages (from-to)737-747
Number of pages11
JournalJournal of Alzheimer's Disease
Volume23
Issue number4
DOIs
Publication statusPublished - 1 Jan 2011

Keywords

  • APOC1
  • apolipoprotein C-I
  • cholesterol
  • cognition and brain
  • memory
  • DENSITY-LIPOPROTEIN RECEPTOR
  • SPORADIC ALZHEIMERS-DISEASE
  • ESTER TRANSFER PROTEIN
  • BLOOD-BRAIN-BARRIER
  • LIVER-X-RECEPTOR
  • E MESSENGER-RNA
  • TRANSGENIC MICE
  • APOC-I
  • GENETIC ASSOCIATION
  • HEME OXYGENASE-1

Cite this

Berbee, J. F., Vanmierlo, T., Abildayeva, K., Blokland, A., Jansen, P. J., Lütjohann, D., Gautier, T., Sijbrands, E., Prickaerts, J., Hadfoune, M. H., Ramaekers, F. C. S., Kuipers, F., Rensen, P. C., & Mulder, M. (2011). Apolipoprotein CI knock-out mice display impaired memory functions. Journal of Alzheimer's Disease, 23(4), 737-747. https://doi.org/10.3233/JAD-2010-100576