Effect of acute ischemic stroke in 3xTg-AD mouse model of Alzheimer's disease

Alzheimer's disease (AD) and acute ischemic stroke (AIS) are major cerebral pathologies that impose significant social and economic burdens. The high prevalence of multimorbidity in older adults is often attributed to shared risk factors like hypertension, smoking, and diabetes. AIS, through vascular complications and acute inflammation, may accelerate AD pathology and cognitive decline. However, the extent to which AIS exacerbates AD-related neurodegeneration remains unclear. To investigate this interaction, we used the 3xTg-AD mouse model, which exhibits both amyloid-beta (Aβ) and Tau pathologies, to assess the impact of AIS on AD progression. Eight-month-old control B6129SF2/J and 3xTg-AD mice underwent a 45-min transient middle cerebral artery occlusion (MCAo) followed by reperfusion at different time points to induce ischemic stroke. Mice were sacrificed at 3- and 50-days post-stroke, and brain tissues were analyzed via western blot and immunohistochemistry to evaluate protein changes. Additionally, we assessed long-term functional impairments in these mice. Our findings show that 3xTg-AD mice had higher infarct volumes, Aβ accumulation, and amyloid-beta precursor protein (AβPP) levels while the total Tau levels were reduced as compared with wild-type (WT) control B6129SF2/J mice after AIS. Functionally, 3xTg-AD mice showed more severe impairments in spatial memory and locomotion tasks post-stroke. Overall, our study demonstrates that AIS worsens AD pathology in 3xTg-AD mice, leading to greater neurodegeneration, functional decline, and increased mortality. These findings highlight the detrimental impact of cerebrovascular events on AD progression, emphasizing the need for targeted interventions in stroke-affected AD patients.