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International Journal of Alzheimer’s Disease
Volume 2011 (2011), Article ID 792070, 8 pages
Research Article

ApoE4-Driven Accumulation of Intraneuronal Oligomerized Aβ42 following Activation of the Amyloid Cascade In Vivo Is Mediated by a Gain of Function

1Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
2George P. and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555-0857, USA
3Departments of Neurosciences and Pathology, University of California San Diego, La Jolla, CA 92093-0624, USA

Received 4 October 2010; Revised 21 November 2010; Accepted 3 December 2010

Academic Editor: Katsuhiko Yanagisawa

Copyright © 2011 Lia Zepa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.