Cellular senescence as a potential sex-specific driver of small vessel disease and post-stroke cognitive impairment in late adulthood - PROJECT SUMMARY/ABSTRACT Stroke is the leading cause of long-term disability in the United States and is the third leading cause of death in women, and the fifth in men. Through improvements in acute ischemic stroke management with increased use of thrombolytics and thrombectomy, there are a growing number of patients surviving ischemic stroke. Recent findings suggest that ~65% of stroke survivors live with some degree of cognitive impairment that negatively impacts their quality of life. Compared with men, women experience worse post-stroke functional and quality- of-life outcomes. Reasons for this disproportionate stroke burden are not clear. Cerebral small vessel disease (SVD), such as cerebral amyloid angiopathy (CAA), is highly prevalent in older adulthood and a common cause of stroke, mild cognitive impairment, and dementia. The female sex is associated with more severe vascular brain lesions secondary to SVD, and long-term cognitive deterioration after acute lacunar stroke. Indeed, the underlying pathological mechanisms and relationship between SVD and ischemic stroke have remained elusive, in part, because animal models rarely examine stroke pathophysiology in the setting of SVD. The long-term sequelae and how they differ between sexes have been largely ignored. Our proposal aims to understand the chronicity of events, secondary injury mechanisms, and disease phenotypes underlying the chronic phase of stroke. We hypothesize that stroke causes accelerated brain aging in a sex-specific manner, with postmenopausal females having worse neurological outcomes. We further hypothesize that brain injury- induced senescence is a key driver of inflammatory neurodegeneration. Our preliminary data suggest that ischemic stroke is a chronic neurodegenerative disease with non-resolving inflammation and cognitive deficits that continue to worsen over time. We identified senescent microglia as potential culprits. To explore this further, Aim 1 will examine the chronic and evolving neurological consequences of SVD following stroke. Male and female Tg-SwDI and wildtype C57Bl/6 control mice (12-months-old) will undergo middle cerebral artery occlusion or sham surgery and be evaluated longitudinally using magnetic resonance imaging and a battery of behavioral tests at 1-, 3-, and 6-months post-stroke. Biomarkers of aging/disease will be examined to generate a temporal map of chronic pathologies. In Aim 2, we propose that delayed treatment strategies targeting the elimination of senescent cells will reduce chronic inflammation, vascular amyloidosis, white matter loss, neurodegeneration, and cognitive decline. Using the same paradigm outlined above, we will administer a senolytic combinatorial therapy, dasatinib plus quercetin, starting at 1-month post-stroke, to determine whether mitigating secondary injury can improve CAA disease course and functional outcomes. In summary, the proposed aims will determine if injury-induced senescence is responsible for accelerated brain aging after stroke, and whether delayed treatment strategies can slow cognitive decline and promote healthy aging.
