title: ApoE4-Driven Accumulation of Intraneuronal Oligomerized Aβ42 following Activation of the Amyloid Cascade In Vivo Is Mediated by a Gain of Function.
abstract: Activating the amyloid cascade by inhibiting the Aβ-degrading enzyme neprilysin in targeted replacement mice, which express either apoE4 or apoE3, results in the specific accumulation of oligomerized Aβ42 in hippocampal CA1 neurons of the apoE4 mice. We presently investigated the extent to which the apoE4-driven accumulation of Aβ42 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 Aβ42 in hippocampal CA1 neurons of the apoE4 mice but not of either the corresponding apoE3 mice or apoE-deficient mice. At 10 days, Aβ42 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 Aβ42 and oligomerized Aβ42 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 Aβ42 which is mediated via a gain of function property of apoE4.
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Lia
authors.initials: L
authors.lastname: Zepa
authors.forename: Moran
authors.initials: M
authors.lastname: Frenkel
authors.forename: Haim
authors.initials: H
authors.lastname: Belinson
authors.forename: Zehavit
authors.initials: Z
authors.lastname: Kariv-Inbal
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Michaelson