Mechanisms of the signaling metabolite β-hydroxybutyrate in Alzheimer's disease and the aging brain - PROJECT SUMMARY/ABSTRACT Aging is the strongest risk factor for Alzheimer’s disease, and the deleterious effects of both aging and Alzheimer’s disease on the brain result in untold personal, family, and societal impacts. Yet the effects of aging can be studied and manipulated biologically, providing hope for impactful new therapies that target mechanisms of aging such as cellular metabolism. Cellular metabolism is linked to other mechanisms of aging via signaling metabolites, small molecules with routine functions in cellular energy metabolism that also act as signals to regulate diverse cellular pathways in response to changes in energy state. The ketones bodies, including beta- hydroxybutyrate (BHB), are examples of signaling metabolites that have important roles in regulating mechanisms of aging. Production of ketone bodies is highest under conditions of glucose scarcity, such as during fasting, carbohydrate restriction, or exercise, where they provide a non-glucose source of cellular energy to organs including the brain. Yet a small quantity of ketone bodies are also produced constitutively, when glucose is abundant. Ketone bodies can offset acquired cellular energy deficits in diseases of aging such as heart failure and AD, as well as regulating gene expression, inflammation, senescence, and other cellular activities that are important for brain aging and AD. Previously, we demonstrated that the ketone-producing ketogenic diet (KD) improves survival and prevents age- and AD-related memory decline in both wild-type and hAPP AD model mice. We elucidated a new proteostatic function for BHB relevant to AD, promoting the clearance of misfolded proteins from the brain. We further demonstrated that KD and BHB improve synaptic function in aging by remodeling the synaptic proteome and activating the protein kinase A signaling pathway. Further, we showed that KD and BHB ameliorate aging- related neuroinflammation. Finally, we described sex- and tissue-specific declines in ketone metabolism with age. However, a large gap remains in understanding how the endogenous, constitutive ketogenic system affects brain aging and AD and if this system, both within the brain and systemically, can be a target for drug discovery to prevent or treat AD. This project combines expertise in aging, AD, and ketone biology to carry out mechanistic studies using transgenic mouse and human cell models. The project examines two mechanisms: one that is highly specific to ketone metabolism within the brain (Aim 1), and another involving inter-organ cross-talk of lipid and ketone metabolism between the gut, liver, and brain (Aim 2). The mechanistic framework it generates will directly inform translational studies and drug discovery for AD (Aim 3). These data will help us establish cell-specificity and inter-tissue criteria for designing effective interventions, and identify new candidate molecular inventions to target the endogenous ketogenic system to ameliorate aging and AD.
