ApoE4-driven accumulation of intraneuronal oligomerized Aß42 following activation of the amyloid cascade in vivo is mediated by a gain of function

Lia Zepa, Moran Frenkel, Haim Belinson, Zehavit Kariv-Inbal, Rakez Kayed, Eliezer Masliah, Daniel M. Michaelson

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Abstract

Activating the amyloid cascade by inhibiting the Aß-degrading enzyme neprilysin in targeted replacement mice, which express either apoE4 or apoE3, results in the specific accumulation of oligomerized Aß42 in hippocampal CA1 neurons of the apoE4 mice. We presently investigated the extent to which the apoE4-driven accumulation of Aß42 and the resulting mitochondrial pathology are due to either gain or loss of function. This revealed that inhibition of neprilysin for one week triggers the accumulation of Aß42 in hippocampal CA1 neurons of the apoE4 mice but not of either the corresponding apoE3 mice or apoE-deficient mice. At 10 days, Aß42 also accumulated in the CA1 neurons of the apoE-deficient mice but not in those of the apoE3 mice. Mitochondrial pathology, which in the apoE4 mice is an early pathological consequence following inhibition of neprilyisn, also occurs in the apoE-deficient but not in the apoE3 mice and the magnitude of this effect correlates with the levels of accumulated Aß42 and oligomerized Aß42 in these mice. These findings suggest that the rate-limiting step in the pathological effects of apoE4 on CA1 neurons is the accumulation of intracellular oligomerized Aß42 which is mediated via a gain of function property of apoE4.

Original languageEnglish (US)
Article number792070
JournalInternational Journal of Alzheimer's Disease
DOIs
StatePublished - Apr 6 2011

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ASJC Scopus subject areas

  • Aging
  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience
  • Behavioral Neuroscience

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