Project Summary Ischemic stroke is one of the leading causes of dementia, with 30-40% of stroke patients developing significant dementia within 10 years. However, the mechanistic link between ischemic injury and subsequent development of vascular dementia remains incompletely understood. We do know that additional stroke-triggered mechanisms are contributing, as even after controlling for stroke risk factors (age, hypertension, diabetes, myocardial infarction, congestive heart failure, cerebral atrophy, white matter changes, and recurrent strokes), the occurrence of cerebral infarction itself independently increases dementia risk. Recent work from the Buckwalter lab demonstrated that ischemic injuries induce a persistent, chronic inflammatory response in the CNS remote from the initial lesion site that is critical for later development of cognitive decline. However, the source and identity of molecular antigens that sustain the inflammatory response are not known. Immunostaining for innate and adaptive immune cells after stroke show prominent localization where the white matter tracts have undergone Wallerian axon degeneration. This raises the possibility that axonal proteins are the major source of antigens that stimulate the neuro-inflammatory response, and that axonal degeneration is a necessary step to trigger and maintain the chronic inflammatory state that ultimately leads to development of post-stroke cognitive impairment. Taking advantage of a mutant mouse strain that I previously identified to be resistant to axonal degeneration following ischemic injuries, I will test the hypothesis that preventing axonal degeneration is necessary to (1) attenuate the inflammatory response after stroke, and (2) mitigate the development of post-stroke dementia. These genetic and animal disease models provide powerful approaches to ask whether functional preservation of axons mitigates immune cell infiltration and activation after stroke, and whether this subsequently prevents the development of post-stroke dementia. The proposed work will provide mechanistic insight into how ischemic injuries lead to vascular dementia, and help uncover therapeutic targets to delay or attenuate the progression of a major stroke-related comorbidity.