Persistent neurological and cerebrovascular deficits following ischemic stroke in a transgenic mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundTissue nonspecific alkaline phosphatase (TNAP) is one of the most abundant enzymes in brain cerebral microvessels, although its function in human health and disease remains less clear. Our lab has demonstrated that the loss of TNAP activity in cerebral microvessels is linked to diminished blood‐brain barrier function and decreased cerebrovascular integrity in mouse models of sepsis, ischemic stroke, and Alzheimer’s disease (AD). While it is widely known that stroke and AD are comorbid, the relationship between existing AD and its impact on outcomes following ischemic stroke is less clear. The goal of this study was to assess the impact of a moderate cortical ischemic stroke on post‐stroke sensorimotor deficits and AD‐like neuropathology in a mouse model of AD. We hypothesized that post‐stroke loss of TNAP activity is accompanied by a persistent loss of cerebral blood flow (CBF), exacerbated sensorimotor deficits, elevated neuroinflammation, and increased beta‐amyloid deposition.MethodMale and female APPSwID/iNOS‐/‐ (CVN‐AD) mice, 10‐12 months old, were subjected to a cortical photothrombotic stroke (AD+PTS) or sham (AD+sham) surgery and euthanized at seven days post‐stroke. Daily neurological scores, corner test, and rotarod were performed to assess sensorimotor deficits. CBF was assessed by laser speckle contrast imaging (LSCI) prior to euthanasia. Saline‐perfused and 4% paraformaldehyde fixed tissue sections underwent histological staining to quantify infarct volume, cerebral microvessel TNAP activity, and microhemorrhages. Immunostaining assessed astrogliosis, via glial fibrillary acidic protein (GFAP), microgliosis, via Iba‐1, and beta‐amyloid deposition.ResultIschemic stroke impaired performance on the corner test (p=0.0054) and rotarod (p=0.0138) in PTS+AD compared to sham+AD mice. At seven days post‐stroke CBF was diminished (p<0.0001) while Iba‐1 immunolabeling revealed increased microgliosis in the ipsilateral cortex (p<0.0001) and ipsilateral hippocampal CA1 (p=0.0022) in PTS+AD compared to sham+AD mice. A preliminary quantification of TNAP activity in the non‐infarcted ipsilateral hemisphere revealed a trending decrease in PTS+AD mice. No sex differences were observed.ConclusionSensorimotor deficits and microgliosis were increased while CBF was decreased at seven days post‐stroke in PTS+AD compared to sham+AD mice. These and other indices will be compared with age‐matched wild‐type mice in ongoing experiments.