PROPOSAL SUMMARY / ABSTRACT Multiple lines of clinical evidence demonstrate a link between pneumonia, cognitive impairment, and dementia in the elderly. The mechanisms underlying this susceptibility, however, remain unclear. In this proposal, we will test the hypothesis that loss of proteostasis in old microglia results in a persistent maladaptive response to immune insult that precludes recovery of neuronal plasticity and cognitive capacity after severe viral pneumonia. Toward this aim, the Budinger/Misharin Laboratory has developed a murine model of pneumonia using influenza A virus, which we will use to compare cognitive recovery in young and old animals and models of Alzheimer's disease (AD). Our preliminary transcriptomics data from bulk brain tissue and flow-sorted microglia suggests that microglia in old animals develop significant proteostasis dysfunction, and adopt a pro- inflammatory phenotype in the steady state. This is exacerbated by persistent activation of the integrated stress response after pneumonia, in addition to aberrant increases in antigen presentation and gliogenic markers. We hypothesize that microglial proteostasis deficits in aging and in AD may impair homeostatic function and “prime” an aberrant response to infection, leading to neurodegeneration and cognitive impairment after insult. In this proposal, we will first test whether microglia are necessary for the initiation of cognitive impairment in murine models of aging and AD, using pharmacological ablation. We will then determine whether cognitive deficits after pneumonia in aging and AD can be rescued through inhibition of the ISR with the small- molecule inhibitor ISRIB. Finally, we will determine whether activation of the ISR in microglia, alone, is necessary or sufficient for the precipitation of cognitive impairment in AD using genetic manipulation of the ISR effector Atf4. This study will help to critically evaluate the role of infection in the development of sporadic dementia, and may aid in the development of prophylactic therapies for age-related cognitive impairment.