Project Summary Tauopathies including Alzheimer's Disease (AD) and frontotemporal dementia (FTD) affect a third of the world population aged over 65. To cope with this health crisis, industrial and academic laboratories have been trying to develop drugs. These efforts have resulted in hundreds of clinical trials, but the success has been limited to only slowing the disease by a handful. The failure points our lack of knowledge of how these diseases set off. Therefore, there is a need to better understand the biochemical processes in the early stage of these diseases. It is possible that regulatory imbalances brought by many factors rendering these diseases highly heterogeneous. To address these complex issues, it is critical to identify new factors contributing to the development of tauopathies. This proposal will determine if a secretory protein factor, chromogranin A (CgA), plays any role in tauopathies. CgA is an acidic glycoprotein synthesized and stored in hormone storage granules of endocrine cells and neurons acting as a regulator of neurotransmitter. It plays an important role in maintaining tissue homeostasis, inflammation, and insulin sensitivity. CgA concentration was reported to be high in the CSF of AD patients and was frequently observed in Aβ plaques surrounded by activated microglia and stimulates the release of cytotoxins. These previous reports, however, are based on in vitro experiments in cultured cells and no real progress has been made to understand CgA's role in AD in vivo. Moreover, whether CgA plays a role in tau pathogenesis is completely unknown. Three research groups with expertise in tauopathy, CgA physiology, and inflammation will work together to investigate if and how CgA affects cognition, neuroinflammation, and metabolism of PS19 transgenic mice. We have gathered preliminary information showing that i) PS19 mice are insulin-resistant; ii) CgA is overexpressed in PS19 and iii) an inflammatory pathway is activated in PS19 mice brain. Our data along with published reports led us to hypothesize that overexpression of CgA is responsible for i) metabolic stress, ii) neuroinflammation and iii) neurotransmitter imbalance. These abnormalities are intimately associated with heightened pathological tau accumulation resulting in the full-blown disease. To test our hypothesis, we will generate PS19/Chga-/- and PS19/Chga-/+ mice, and determine if the depletion of CgA ameliorates neurodegeneration by comparing i) pathological tau accumulation and propagation, ii) neuroinflammation, iii) cognitive function, and iv) metabolic phenotype and longevity, in these and age- matched PS19/Chga+/+ (PS19) and non-transgenic/Chga+/+ (wild type) mice.