Genetic restoration of plasma apoe improves cognition and partially restores synaptic defects in ApoE-deficient mice

Courtney Lane-Donovan, Wen Mai Wong, Murat S. Durakoglugil, Catherine R. Wasser, Shan Jiang, Xunde Xian, Joachim Herz

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ÷4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function. To bypass the effect of ApoE loss on plasma lipids, we generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain, allowing us to study brain ApoE loss in the context of a normal plasma lipid profile. We found that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice. Moreover, we found that the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain.

Original languageEnglish (US)
Pages (from-to)10141-10150
Number of pages10
JournalJournal of Neuroscience
Volume36
Issue number39
DOIs
StatePublished - Sep 28 2016

Keywords

  • Alzheimer’s
  • ApoE
  • ApoE4
  • Cognition
  • Dementia

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Genetic restoration of plasma apoe improves cognition and partially restores synaptic defects in ApoE-deficient mice'. Together they form a unique fingerprint.

  • Cite this