Glycolysis and rodent models of Alzheimer's disease

Abstract Alzheimer’s disease (AD) is an inexorable and devastating neurodegenerative disease affecting mil- lions of Americans. There are no therapies that could stop or reverse the progression of Alzheimer’s disease, in part because the basic factors driving neuronal death and dysfunction are unknown. There is a critical need to better understand the basic biology of AD in order to develop new disease-modify- ing treatments. A key contributing factor to AD is impaired glucose metabolism. Several observations support this con- clusion. First, aging is a major AD risk factor that impairs brain glucose metabolism, reduces mitochon- drial biogenesis, and decreases ATP levels. Second, neurodegeneration in AD can be directly quanti- fied by imaging glucose metabolism via techniques such as 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Third, metabolic diseases such as obesity and diabetes are key risk fac- tors for AD. Fourth, interventions that improve metabolism such as exercise, calorie restriction, and treatment for diabetes can mitigate the risk and progression of AD. Last but not least, Aerobic glycoly- sis, which can be measured by FDG-PET and 15O-PET in vivo imaging, is compromised in patients with Alzheimer’s disease. Despite these data, it is unknown how glucose metabolism contributes to neurodegenerative pro- cesses in AD. Our recent work demonstrated that we can enhance one aspect of brain glucose metab- olism, glycolysis, via an existing drug, terazosin (TZ). This drug is an alpha-1 antagonist, but also acti- vates the first ATP-generating step of glycolysis, phosphoglycerate kinase-1 (PGK1). In this proposal, we will interrogate glycolysis in rodent models of AD, including tau and amyloid mouse lines, while measuring metabolomics, cognitive function, 18F-FDG-PET, and protein aggregation. Our overall hy- pothesis is that glycolysis critically regulates neurodegeneration in AD. Our specific aims investigate if disrupting glycolysis affects rodent AD models and if improving glycolysis mitigates neurodegeneration in AD. Because this is a fundamental mechanism, our work could have far-reaching impact for neuro- degenerative diseases, and could be instrumental in inspiring novel disease-modifying therapies for AD and related diseases.