Pilot: Microbial-Derived Exerkines in Alzheimer's Disease: Can Pipecolic Acid and Succinate Recapitulate Exercise Benefits?

Program Director/Principal Investigator (Last, First, Middle): Wen, Yuan PROJECT SUMMARY (See instructions): Alzheimer''s disease (AD) represents a growing public health challenge with limited effective treatments. Exercise has emerged as a promising intervention that can decrease amyloid-β plaque burden, improve cognition, and attenuate neuroinflammation. However, many AD patients have mobility limitations that prevent exercise participation. Our laboratory has identified that some exercise benefits are mediated through microbial-derived exerkines (MDEs) produced by the gut microbiome. We recently demonstrated that pipecolic acid and succinate (PAS) are key MDEs elevated after exercise that confer beneficial effects on skeletal muscle metabolism in sedentary mice. This study aims to determine whether oral administration of PAS can mimic exercise-induced benefits on CNS metabolism and AD pathology in the 3xTg-AD mouse model. We will compare three experimental groups: sedentary controls, exercise-trained mice, and sedentary mice receiving PAS supplementation. We will assess whether PAS administration reduces AD pathological hallmarks, attenuates neuroinflammation, preserves cognitive function, and induces metabolic changes that overlap with exercise-induced CNS metabolic adaptations. For comprehensive metabolic analysis, we have consulted with Dr. Lance Johnson, whose metabolomics core will perform targeted profiling of key metabolites including pipecolate, succinate, GABA, and glutamate. Additionally, we have collaborated with Dr. Samir Patel to utilize the Mitochondrial Bioenergetics Core for analysis of brain tissue bioenergetics using Seahorse and Oroboros technologies. This research addresses a significant gap in understanding how MDEs influence CNS metabolism in AD and has direct translational potential, as identifying post-biotic compounds that mimic exercise benefits could lead to novel therapeutic strategies for AD patients unable to participate in exercise programs. RELEVANCE (See instructions): This research investigates whether two compounds naturally produced by gut bacteria during exercise could help treat Alzheimer''s disease when taken as supplements. The study is particularly important because many Alzheimer''s patients cannot exercise due to mobility limitations, so if these compounds can provide the same brain-protective benefits as exercise, they could offer a new treatment option for patients who are unable to be physically active. PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page) Project/Performance Site Primary Location Organizational Name: University of Kentucky Research Foundation DUNS: H1HYA8Z1NTM5 Street 1: 500 South Limestone Street 2: 109 Kinkaid Hall City: Lexington County: Fayette State: KY Province: Country: USA Zip/Postal Code: 40526-0001 Project/Performance Site Congressional Districts: KY-006 Additional Project/Performance Site Location Organizational Name: DUNS: Street 1: Street 2: City: County: State: Province: Country: Zip/Postal Code: Project/Performance Site Congressional Districts: Page 2 OMB No. 0925-0001 PHS 398 (Rev. 03/2020 Approved Through 02/28/2023) Form Page 2