Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia and is frequently found in association with Alzheimer’s disease and Alzheimer’s disease-related dementias. Recent studies in intracerebral hemorrhage (ICH) patients who survive show an alarming rate of progression to dementia, within only a few months of injury- even in young people. The mechanisms for this rapid progression to dementia are unknown. Receptor interacting protein kinase (RIPK)-1 is a serine/threonine kinase that promotes cognitive deficits in models of dementia and neurodegeneration. In a collagenase ICH model, RIPK1 was activated in cerebral endothelium in the chronic period, and RIPK1 kinase dead mice were completely protected against chronic blood-brain barrier damage, a major mechanism of ADRD and VCID. These observations suggest that RIPK1 is a potential cause of VCID in ICH patients. ICH induces well characterized mechanisms of cognitive dysfunction, including (1) increased levels of phospho-eif2 alpha consistent with an integrated stress response, (2) increased production of processed IL-1 beta in neurons, and (3) persistent BBB damage at 35 days, that are exquisitely dependent on RIPK1 kinase activity. Strikingly, kinase dead RIPK1D138N/D138N → WT bone marrow chimeras were protected against ICH-induced cognitive deficits, supporting a role for RIPK1 in hematopoietic cells, whereas brain RIPK1 drove persistent BBB damage. We hypothesize that RIPK1 causes VCID after ICH via hematopoietic cells which induce activation of the integrated stress response and NLRP1 inflammasome in neurons and endothelium, and via brain endothelium by driving persistent BBB damage. To test these hypotheses, we propose three Specific Aims: Aim 1: Define peripheral mechanisms of early RIPK1-dependent responses to ICH via immune cell activation. Aim 2: Identify brain cell types that mediate RIPK1 kinase-dependent motor, cognitive, and BBB dysfunction after ICH. Aim 3: Define cell-specific mechanisms by which RIPK1 promotes persistent cognitive and blood-brain barrier dysfunction after ICH. Use of novel cell specific inducible RIPK1 kinase dead mice will allow us to test whether RIPK1 inhibition long after ICH can rescue cognitive deficits and BBB damage. Successful completion of the Aims is expected to provide scientific justification for clinical trials using RIPK1 kinase inhibitors in patients in the chronic period of ICH.
