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

Traumatic brain injury (TBI) is an environmental risk factor for Alzheimer's disease (AD). Increased brain concentrations of amyloid-beta (A beta) 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 A beta and amenable to simvastatin therapy. CBF was measured 3 days and 3 weeks after controlled cortical impact (CCI) injury in transgenic human A beta-expressing APP(NLh/NLh) mice compared to murine A beta-expressing C57Bl/6J wild types. Compared to uninjured littermates, CBF was reduced in the cortex of the injured hemisphere in both A beta transgenics and wild types; deficits were more pronounced in the transgenic group, which exhibited injury-induced increased concentrations of human A beta. In the hemisphere contralateral to CCI, CBF levels were stable in A beta transgenic mice but increased in wild-type mice, both relative to uninjured littermates. Post-injury treatment of A beta transgenic mice with simvastatin lowered brain A beta 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.