Influence of gut on metabolism and cognition in Alzheimer's disease.

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PROJECT SUMMARY: Alzheimer’s disease (AD) is the most common cause of dementia and the third leading cause of death in older adults. In addition to cognitive impairment, AD is associated with neuropathology, impaired metabolic function and gut microbiome dysbiosis. However, the relationships between gut health (including the gut microbiome), metabolism and cognitive decline remains largely unknown, despite strong evidence that the gut-brain-axis is an important intermediary in neurodegenerative disease. Moreover, normal aging also influences both gut microbiome composition and peripheral metabolic health, demonstrating the importance of including geroscience as a factor. Gut dysbiosis can result in impaired insulin resistance as well as obesity, both of which increase the risk of developing AD. Therefore, the long term goal of this project is to elucidate how altered gut microbiome composition can influence cognitive outcomes in an aged rat model of AD to identify potential targets for therapeutic intervention. The overall objective is to investigate whether the gut is able to exert its influence over cognition through metabolic intermediates, as the gut microbiome directly influences metabolite production and energy homeostasis. The rationale for this project is that very few, if any, strategies directly targeting brain function have been able to prevent or delay cognitive impairment with AD to date. This line of investigation is innovative in that it suggests a peripheral target, rather than targeting the brain directly, for the alleviation of cognitive symptoms by utilizing the strong, reciprocal link between gut and brain function. Our preliminary data indicates the TgF344-AD rat model mimics the cognitive decline observed with AD, as well as the peripheral metabolic impairments and gut dysbiosis associated AD. The proposed experiments will build on these findings and test the central hypothesis that AD-associated gut dysbiosis negatively influences metabolic function, thereby impairing cognitive function through an impaired ability to properly utilize and respond to energy metabolism. Data from humans with AD, as well as our preliminary data, suggest AD-associated gut dysbiosis negatively influences butyrate production. Depletion of butyrate, the most abundant metabolite produced by the gut microbiome, is associated with many metabolic diseases including diabetes and obesity, both of which are commonly associated with AD. Supplementation of butyrate in rodent models can improve insulin sensitivity, upregulate BDNF and thereby neurogenesis and promote a lean phenotype. Butyrate improves brain health and metabolism, gut health through supporting the gastrointestinal lining quality and influences microbiome composition. These synergistic effects make systemic butyrate a therapeutic strategy, or one component of an effective strategy, with high potential to ameliorate many AD-related impairments in function. Collectively, these experiments will determine if the gut microbiome influences cognitive outcomes in aged AD-model rats through a metabolic intermediary and whether this can be ameliorated through probiotic supplementation.