Summary: Despite enormous resources being committed to study Alzheimer’s disease (AD) there is no effective treatment or cure. One of the difficulties in developing treatments is the lack of animal models that recapitulate human sporadic disease. The goal of this project is to apply the power of comparative biology to develop novel approaches and animal models for AD. We will focus on two rodent species, the naked mole rat (NMR) and Octodon degus (degu) that represent high resistance to AD (NMR) and susceptibility to sporadic onset AD (degu). We expect that these novel approaches will uncover new mechanisms of AD and AD resistance and provide the community with animal models and datasets for future research. In the current funding cycle, we made significant progress in understanding mechanisms of naked mole rat longevity. We demonstrated that NMRs are resistant to osteoarthritis and do not undergo thymic involution. We built epigenetic clocks for NMRs and showed that NMR queens age more slowly. We built a single cell atlas of the NMR hematopoietic system and identified multiple neotenic traits. We previously discovered that naked mole rats have very high levels of high molecular weight hyaluronan (HMW-HA) in their tissues. Excitingly, we now show that mice expressing naked mole rat hyaluronan synthase 2 gene (nmrHAS2) have longer lifespan and healthspan and are protected from inflammation. Funded by an administrative supplement, we expanded our research into the field of AD. Our preliminary data suggest that the nmrHAS2 transgene also protects mice from AD. We also established a colony of degu, a rodent that spontaneously develops AD-like pathology, and discovered that degus are naturally deficient in methionine sulfoxide reductase (MSR) function, which protects methionines from oxidation. This result suggests a novel mechanism for sporadic AD: we hypothesize that in sporadic AD low MSR activity leads to increased methionine oxidation which accelerates the formation of protein aggregates. Project 2 will ask the following questions: What is the mechanism of AD resistance in the NMR? Does elevating HMW- HA, genetically or pharmacologically, protect from AD and how? What is the mechanism of sporadic AD in degu? Does MSR deficiency lead to AD in degu, mouse, and human? Our aims are: (1) To uncover novel mechanisms of AD resistance in the NMR. We will perform transcriptome and proteome comparisons between mouse, NMR, and a short-lived NMR relative, Damaraland mole rat (DMR). We will further investigate the role of HMW-HA in protecting from AD and test whether pharmacological agents that increase HA protect from AD. (2) We will develop degu as a model for AD. We will develop behavioral tests for degu and perform molecular characterization of degu brains and peripheral tissues. We will examine the role of MSR in AD pathology in degu, mouse models of MSR deficiency, and in human brains and induced neurons from AD patients. With Projects 1 and 3 we will e...