Targeting white matter microgliosis using minocycline in a co‐morbid preclinical rat model of Alzheimer’s disease and stroke

Abstract

Current literature indicates a potential synergistic interaction between stroke and Alzheimer’s disease (AD). White matter (WM) inflammation, which is commonly triggered by cerebrovascular disease and AD, disrupts the normal function of white matter; and can trigger and exacerbate dementia‐type symptoms such as memory loss and executive dysfunction. Recent work in our lab demonstrated, for the first time, a link between stroke, AD‐related pathology, and WM inflammation. A unilateral lacunar stroke induction in a comorbid rat model of AD and stroke resulted in microglial activation within the WM tracts and subsequent impairment in behavioural flexibility, an important component of executive function. As such, the aim of the current study was to evaluate the effect of microglia targeting on WM pathology, executive function, learning, and memory in the co‐morbid rat model of AD (TgAPP21) and stroke. Minocycline, a tetracycline‐class antibiotic and an anti‐inflammatory drug, has been shown to decrease apoptosis, inflammation, and microglial activation following cerebrovascular injury. To study the behavioural outcomes of minocycline treatment, TgAPP21 rats received an endothelin‐1‐induced subcortical stroke at the age of 8 months. Following stroke, animals received intraperitoneal injections of minocycline or saline twice daily for four days to supress microglial activation. Cognitive behavioural flexibility post‐stroke was analyzed using set‐shifting operant conditioning test, while spatial learning and memory were assessed using Morris water maze. Immunohistochemistry was performed to evaluate the extent of microglial activation by detection of OX‐6 positive microglia in corpus callosum, internal capsule, and hippocampus. Minocycline treatment significantly decreased the number of errors committed by TgAPP21 rats on the visual cue component of the set‐shifting test, suggesting improved learning of the original visual cue task. However, minocycline also impaired animals’ ability to undergo an extra‐dimensional strategy shift from the original visual cue to a new spatial cue task, suggesting impaired behavioural flexibility. Further, minocycline treatment showed no significant effect on learning and memory of the Morris water maze task in TgAPP21 rats. Collectively, the data indicate that minocycline has distinct effects on the learning component of set‐shifting and Morris water maze tests, though further histological evaluation of OX‐6 positive microglia within WM tracts and hippocampus will contextualize current findings.Support or Funding InformationNatural Sciences and Engineering Research Council (NSERC), Canadian Institutes of Health Research (CIHR), Canadian Foundation for Innovation (CFI), Canadian Consortium for Neurodegeneration and Aging (CCNA)