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The Journal of Neuroscience, January 15, 2002, 22(2):446-454

Repetitive Mild Brain Trauma Accelerates A Deposition, Lipid Peroxidation, and Cognitive Impairment in a Transgenic Mouse Model of Alzheimer Amyloidosis

Kunihiro Uryu^{1, *}, Helmut Laurer^{2, *}, Tracy McIntosh², Domenico Praticò³, Daniel Martinez¹, Susan Leight¹, Virginia M.-Y. Lee¹, and John Q. Trojanowski¹

Departments of ¹ Pathology and Laboratory Medicine, ² Neurosurgery, and ³ Pharmacology, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283

Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known how TBI contributes to the onset or progression of this common late life dementia. To address this question, we studied neuropathological and behavioral consequences of single versus repetitive mild TBI (mTBI) in transgenic (Tg) mice (Tg2576) that express mutant human A precursor protein, and we demonstrate elevated brain A levels and increased A deposition. Nine-month-old Tg2576 and wild-type mice were subjected to single (n = 15) or repetitive (n = 39) mTBI or sham treatment (n = 37). At 2 d and 9 and 16 weeks after treatment, we assessed brain A deposits and levels in addition to brain and urine isoprostanes generated by lipid peroxidation in these mice. A subset of mice also was studied behaviorally at 16 weeks after injury. Repetitive but not single mTBI increased A deposition as well as levels of A and isoprostanes only in Tg mice, and repetitive mTBI alone induced cognitive impairments but no motor deficits in these mice. This is the first experimental evidence linking TBI to mechanisms of AD by showing that repetitive TBI accelerates brain A accumulation and oxidative stress, which we suggest could work synergistically to promote the onset or drive the progression of AD. Additional insights into the role of TBI in mechanisms of AD pathobiology could lead to strategies for reducing the risk of AD associated with previous episodes of brain trauma and for preventing progressive brain amyloidosis in AD patients.

Key words: Alzheimer's disease; amyloid plaques; brain injury; head trauma; APP mice; oxidative stress; cognitive function

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^* K.U. and H.L. contributed equally to this work.

Correspondence should be addressed to Dr. John Q. Trojanowski, Center for Neurodegenerative Disease Research, Hospital of University of Pennsylvania/Maloney, Third Floor, Philadelphia, PA 19104-4283. E-mail: trojanow{at}mail.med.upenn.edu.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222446-09$05.00/0

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