Pathogen-induced cellular senescence and blood-brain barrier dysfunction in Alzheimer's Disease

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) remains a devastating illness for which there are limited prevention and treatment options. Vascular endothelial dysfunction as manifested in the loss of the blood brain barrier (BBB) integrity can precede symptomatic cognitive decline in AD patients and thus suggests that vascular pathology may be involved early on in AD development and progression. Endothelial cells (ECs) play several critical roles such as tightly regulating the transport of molecules across the BBB as well as the influx of immune cells which can induce inflammation and thus promote AD. Recent data suggest that viral or bacterial infections can increase the incidence and progression of Alzheimer’s disease. There is also growing evidence that premature cellular senescence impairs blood brain barrier function and promotes neuroinflammation. However, the mechanistic roles of cellular senescence and blood-brain barrier dysfunction in mediating pathogen-induced AD progression remain unclear. Our preliminary data suggests that viral and bacterial pathogens can initiate blood brain barrier dysfunction by direct activation of inflammatory signaling as well as by increased expression of endogenous retroviruses which in turn initiate a cascade of hyperinflammation. We have developed a novel computational algorithm SenePy to analyze cellular senescence in single cell transcriptomic data and found significant increases in cellular senescence associated with expression of endogenous retroviruses in experimental mouse models of Alzheimer’s disease as well as human brains with Alzheimer’s disease We have thus formulated the overall hypothesis that pathogen-induced cellular senescence and blood -brain barrier dysfunction mediate Alzheimer’s disease. The proposed experiments will leverage experimental mouse models of Alzheimer’s disease, molecular characterization of endogenous retrovirus RNA sensing as well as human iPSC models.