Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease

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Project Summary The initiative behind RFA-AG-20-013 was designed to understand the role of aging in the development and etiology of Alzheimer's disease (AD) and related dementias (ADRD). Our work shows that the F1F0-ATP synthase, the mitochondrial complex responsible for ATP synthesis, is a core component of the mechanisms linking aging to ADRD. We found that the experimental Alzheimer's drug candidate J147 targets the F1 subunit of ATP synthase to exert geroprotective and neuroprotective effects. Our most recent data, obtained under this grant, shows that J147 robustly extends lifespan in C. elegans via chromatin remodeling in neurons. Our data further suggest that J147 extends lifespan in C57BL6 mice, remodels lipid metabolism, and shows signs of improving cognitive performance in very old animals (28 months of age). These additional data are consistent with our central hypothesis that mitochondria are a pivotal link between aging and ADRD that is druggable. Mitochondria control synaptic gene expression via epigenetics and are subject to deterioration by age-associated toxicities such as protein misfolding or oxidative stress. Treatment with J147 stabilizes mitochondria against age- associated toxicities and thus extends lifespan and protects from neurodegeneration by allowing the mitochondria to maintain control of synapse-related gene expression. For this supplement, we ask for the funds to extend specific Aim 1 in the parent application which determines how protecting mitochondrial function preserves and restores synapse function in aged mice. We propose to determine how protecting mitochondria by treatment with J147 preserves or improves mitochondrial and synapse integrity in very old (28 months) wild-type C57BL6 mice using cutting-edge 3-dimensional electron microscopy. We will engage the National Center for Microscopy and Imaging Research to generate ultrastructures of mitochondria and synapses using multi-scale - multi-modal quantitative 3D microscopies, new technologies that became available since we submitted the original award. These advanced EM methods allow quantitative comparisons of tissue changes, such as amyloid plaque sizes, locations, and numbers - as well as quantitative analysis of cellular and sub-cellular elements like mitochondria or synaptic vesicles predicted to be influenced by the main action of J147 as an ATP synthase inhibitor. Our preliminary data also show an interesting thickening of the myelin sheath in very old (28 months) J147 treated animals that is most likely associated with the effect of J147 on lipid metabolism.