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The Journal of Neuroscience, December 1, 2002, 22(23):10083-10087

BRIEF COMMUNICATION
Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Richard E. Hartman^{1, 2, 3}, Helmut Laurer⁴, Luca Longhi⁴, Kelly R. Bales⁵, Steven M. Paul^{5, 6}, Tracy K. McIntosh⁴, and David M. Holtzman^{1, 2, 3, 7}

¹  Center for the Study of Nervous System Injury, ² Alzheimer's Disease Research Center, ³ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, ⁴ Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6316, ⁵ Neuroscience Discovery Research, Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285, ⁶ Department of Pharmacology, Toxicology, and Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46285, and ⁷ Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

The 4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid- (A) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP:E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:E/). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. A load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with A-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E/), but thioflavine-S-positive A (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no A deposition at this age. After TBI, all of the A deposits present in PDAPP:E3 and PDAPP:E/ mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E/ mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on A.

Key words: Alzheimer's disease; amyloid; APP; traumatic brain injury; apoE; hippocampus

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222310083-05$05.00/0

This article has been cited by other articles:

				H. Belinson, D. Lev, E. Masliah, and D. M. Michaelson Activation of the Amyloid Cascade in Apolipoprotein E4 Transgenic Mice Induces Lysosomal Activation and Neurodegeneration Resulting in Marked Cognitive Deficits J. Neurosci., April 30, 2008; 28(18): 4690 - 4701. [Abstract] [Full Text] [PDF]

				N Nathoo, R Chetty, J R van Dellen, and G H Barnett Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E Mol. Pathol., June 1, 2003; 56(3): 132 - 136. [Abstract] [Full Text] [PDF]

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