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. 2002 Jan 15;22(2):446-54.
doi: 10.1523/JNEUROSCI.22-02-00446.2002.

Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis

Kunihiro Uryu  1 , Helmut Laurer, Tracy McIntosh, Domenico Praticò, Daniel Martinez, Susan Leight, Virginia M-Y Lee, John Q Trojanowski
Affiliations

Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis

Kunihiro Uryu et al. J Neurosci. .

Abstract

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 Abeta precursor protein, and we demonstrate elevated brain Abeta levels and increased Abeta 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 Abeta 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 Abeta deposition as well as levels of Abeta 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 Abeta 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.

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Figures

Fig. 1.
Fig. 1.
Data from behavioral and motor tests in WT and Tg2576 mice. A, B, Data from the MWM test in WT and Tg mice. Trials were made in consecutive 8 d sessions at 16 weeks after injury. C, Motor function tests performed at 16 weeks after injury. Rep, Repetitive.
Fig. 2.
Fig. 2.
Histological sequelae of single or repetitive (Rep) mTBI and sham treatment in Tg2576 mice. H&E staining with Gomori's iron stain (A, C, E, G) and GFAP staining (B, D, F, H, insets) are shown. Single and repetitive mTBI resulted in no or very mild damage at the impact site in the brain at 2 d (A, B), and 16 weeks (C–H) after the injury. Eachinset indicates a high-power view of the rectangular area shown in the images in B, D, F, andH. Sham treatment resulted in no overt damage (C, D). A, B, Repetitive mTBI (2 d after TBI).C, D, Sham (16 weeks after treatment). E, F, Single mTBI (16 weeks after TBI). G, H, Repetitive mTBI (16 weeks after TBI).
Fig. 3.
Fig. 3.
Amyloid deposition in Tg2576 mice with sham or repetitive (Rep) mTBI (B, D) with 4G8 immunohistochemistry at 9 (A, C) and 16 (B, D) weeks after mTBI. SPs increased in an age-dependent manner in both sham and injured mice, but the largest number of Aβ-positive SPs are seen in the 16 week postrepetitive mTBI mice (D).
Fig. 4.
Fig. 4.
Average percentages of the area occupied by Aβ in three brain areas of interest, including the PHC, SSC, and HP.A, Data from the total number of mice in each group, including male and female for all regions of interest.B, Data in A plotted for each region (n = 4–6). *p < 0.05 in comparison with sham treatment. Rep, Repetitive.
Fig. 5.
Fig. 5.
Concentration of brain Aβ as determined by sandwich ELISA. Aβ1–40 and Aβ1–42 peptides were measured in soluble (A) and insoluble (B) fractions of cortex (CTX), hippocampus (HP), and cerebellum (CBL) from sham and single and repetitive (Rep) mTBI Tg2576 mice (n = 4–6). *p < 0.05; **p < 0.001 in comparison with sham injury.
Fig. 6.
Fig. 6.
Concentration of 8,12-iso-iPF2α-VI in urine (A) and brain (B). Urine was collected at 9, 12, and 16 weeks after TBI or sham treatment. Brain tissue was collected from hippocampus (HP), cortex (CTX), and cerebellum (CBL) at 16 weeks after mTBI or sham treatment. All samples came from Tg2576 mice.Rep, Repetitive.
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