Cerebral blood flow changes after brain injury in human amyloid-beta knock-in mice

Abstract

Traumatic brain injury (TBI) is an environmental risk factor for Alzheimer's disease (AD). Increased brain concentrations of amyloid-β (Aβ) peptides and impaired cerebral blood flow (CBF) are shared pathologic features of TBI and AD and promising therapeutic targets. We used arterial spin-labeling magnetic resonance imaging to examine if CBF changes after TBI are influenced by human Aβ and amenable to simvastatin therapy. CBF was measured 3 days and 3 weeks after controlled cortical impact (CCI) injury in transgenic human Aβ-expressing APP(NLh/NLh) mice compared to murine Aβ-expressing C57Bl/6J wild types. Compared to uninjured littermates, CBF was reduced in the cortex of the injured hemisphere in both Aβ transgenics and wild types; deficits were more pronounced in the transgenic group, which exhibited injury-induced increased concentrations of human Aβ. In the hemisphere contralateral to CCI, CBF levels were stable in Aβ transgenic mice but increased in wild-type mice, both relative to uninjured littermates. Post-injury treatment of Aβ transgenic mice with simvastatin lowered brain Aβ concentrations, attenuated deficits in CBF ipsilateral to injury, restored hyperemia contralateral to injury, and reduced brain tissue loss. Future studies examining long-term effects of simvastatin therapy on CBF and chronic neurodegenerative changes after TBI are warranted.

Figure 1

Coronal brain section through the dorsal hippocampus illustrating regions of interest (ROIs) examined in this study. Left hemisphere taken from Franklin and Paxinos at approximately 2.0 mm caudal to Bregma. Right hemisphere illustrates a cresyl violet-processed section with ROI outlined in color. The color reproduction of this figure is available on the JCBFM journal online. CR, contusion region.

Figure 2

Representative cerebral blood flow (CBF) maps illustrated on coronal views of arterial spin-labeling MR images taken at the level of the dorsal hippocampus from naive and injured C57 and APP^NLh/NLh mice. CBF levels in each region of interest defined in Materials and Methods were quantified and are illustrated in Figure 3. CCI, controlled cortical impact.

Figure 3

Cerebral blood flow (CBF) values in regions of interest in naive and controlled cortical impact injured C57 and APP^NLh/NLh mice (mean±SE). *APP^NLh/NLh<C57, P<0.05; **APP^NLh/NLh<C57, P<0.01; ^†3 days, 3 weeks>naive, P<0.05; ^‡3 days, 3 weeks compared with naive, P<0.01. CR, contusion region.

Figure 4

(A) Representative magnetic resonance image (A, top row) cerebral blood flow (CBF; A, bottom row) maps illustrated in coronal views at the level of the dorsal hippocampus from APP^NLh/NLh mice after controlled cortical impact (CCI) injury and 3 weeks treatment with either vehicle or 3 mg/kg simvastatin. (B) Region of interest CBF values from the two experimental groups with CCI/vehicle (gray bars) and CCI/drug (black bars) treatment. *CCI/drug>CCI/vehicle, P<0.05. CR, contusion region.

Figure 5

Analyses of brain tissue volume in representative magnetic resonance image (MRI) scans ex vivo (MRI images, A; quantification, B) and corresponding histologic sections (photomicrographs, C; quantification, D) from APP^NLh/NLh subjected to controlled cortical impact (CCI) injury and treatment with either vehicle or 3 mg/kg simvastatin for 3 weeks. MRI analysis demonstrates greater tissue preservation in the CCI/drug group. *P<0.05.

Figure 6

Enzyme-linked immunosorbent assay analyses of Aβ1-42 (A) and Aβ1-40 (B) concentrations in the cortex and hippocampus tissue homogenates from C57 and APP^NLh/NLh mice with no injury (naive) or 3 weeks after controlled cortical impact (CCI) injury and administration of either vehicle or 3 mg/kg simvastatin in APP^NLh/NLh mice. *P<0.05.