About 800,000 people in the U.S. experience ischemic stroke annually, a leading cause of cognitive disability. Emerging data has identified new links between stroke and other dementias, such as Alzheimer’s Disease, with about 25–30% of ischemic stroke survivors developing immediate or delayed vascular cognitive impairment and dementia. Platelets mediate ischemic stroke and vascular damage by interacting with neutrophils to increase inflammation, which leads to neuronal death, cognitive dysfunction, and dementia. However, the molecular mechanism by which platelets regulate ischemic stroke and the development of vascular dementia remain unknown. Platelets possess a dynamic transcriptome and mRNAs in platelets are translated to new proteins in signal-dependent fashion. In platelets, one of the primary pathways controlling mRNA translation and associated cellular and metabolic processes is the mechanistic Target of Rapamycin (mTOR). Our preliminary data demonstrate that the mTOR pathway is functional in platelets, and that mTOR controls protein synthesis, including amyloid precursor protein (APP), a key player in the development of dementia. Moreover, our data suggest that targeting mTOR in platelets alters platelet function and improves ischemic and neurological outcomes in stroke. Whether mTOR is activated in platelets during ischemic stroke, and how this influences mRNA translation, cellular/metabolic functions, and outcomes has never before been rigorously examined. We will test the innovative hypothesis that targeting the mTOR pathway in platelets improves neurological and cognitive outcomes following ischemic stroke, thereby reducing the risk of developing vascular dementia. We will employ complementary clinical, in vitro, and in vivo approaches, along with state-of-the-art sequencing techniques to rigorously test this hypothesis. Specific Aim 1 will determine if mTOR activation and mRNA translation are upregulated in platelets during ischemic stroke. We will specifically examine the regulation of APP protein synthesis and other proteins under mTOR control which contribute to neuronal damage and adverse cognitive outcomes. Specific Aim 2 will determine how mTOR activation in platelets regulates functional responses during stroke, including the role of platelet mTOR in regulating inflammation, cerebral blood flow, and blood brain barrier disruption, all known to contribute to the development of vascular dementia. Specific Aim 3 will establish whether targeting mTOR improves ischemic and neurological outcomes in stroke. Successful completion of these aims will 1) identify transcripts under mTOR-dependent control in platelets during stroke; (2) establish whether disruption of mTOR attenuates platelet APP deposition, downstream inflammatory signaling, and blood brain barrier permeability; and (3) determine whether targeting mTOR improves cerebral blood flow and neurological outcomes following stroke. Data generated will significantly increase our u...