Post-stroke cognitive impairment in an Alzheimer’s disease mouse model

Abstract

Ischemic stroke (IS) is a major risk factor for dementia and may accelerate Alzheimer’s disease (AD) progression, but the underlying mechanisms remain unclear. We investigated whether cortical IS influences AD-related pathology, including hippocampal gliosis, neurogenesis, and amyloid deposition, and whether it worsens cognitive decline in a preclinical AD model. Permanent middle cerebral artery occlusion (pMCAO) was induced in 4-month-old wild-type (WT) and triple-transgenic AD (3xTg-AD) mice. Stroke severity and motor function were assessed one week post-surgery, followed by behavioral and histological analyses at the age of 5–6 months. pMCAO produced comparable infarct size and motor outcomes in WT and 3xTg-AD mice, with lesions restricted to the sensorimotor cortex and sparing the hippocampus. Histological analyses revealed reduced hippocampal neurogenesis and mildly increased astrogliosis in 3xTg-AD mice, whereas pMCAO did not significantly affect microgliosis, neurogenesis, or amyloid burden in either genotype. Behaviorally, 3xTg-AD mice showed impaired remote contextual fear memory, consistent with early AD-related deficits. In WT mice, pMCAO impaired contextual memory retrieval when conditioning occurred after stroke, but did not further worsen cognition in 3xTg-AD mice. At the time point examined, early cortical IS did not induce detectable additional AD-related pathology or cognitive impairment in 3xTg-AD mice. Cognitive impairments in 3xTg-AD mice coincided with reduced hippocampal neurogenesis.