Dissecting the molecular mechanism of ketogenic metabolites in AD

About This Grant

PROJECT SUMMARY Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease affecting a total of 6.5 million Americans over the age of 65, with that number growing each year as our population ages. There is currently no prevention nor cure for AD, and only a handful of drugs that slow, but do not stop, the disease’s progression. The AD brain is marked by accumulation of amyloid β plaques, tau neurofibrillary tangles, and lipid droplets. Recent studies report brain and whole-body metabolic dysfunction in AD, to the extent that glucose insensitivity, insulin resistance, and metabolic hormone dysregulation are nascent hallmarks of AD. Additionally, metabolic syndromes such as type 2 diabetes, obesity, and hypertension are significant risk factors for the development of AD. The contemporary understanding of AD as a metabolic disorder has sparked a growing interest in metabolism-based therapy. One such therapy, the ketogenic diet (KD), a high-fat/low-carbohydrate diet, is increasingly being studied in the context of AD and has shown promise in preclinical and clinical trials. However, the potential of the KD as a treatment for AD is marred by variable efficacy, low compliance, and side effects outweighing benefits. The molecular mechanisms by which the KD ameliorates AD pathology are unclear and warrant further study, and potential mechanisms include inhibiting carbohydrate metabolism, increasing fat metabolism, and altering amino acid (AA) metabolism. My F99 phase (Aim 1) of this proposal will focus on β- hydroxybutyrate (BHB), the primary ketone body produced by KDs, which can act on the body in two main ways: metabolism for energy and signaling. I will disentangle these molecular features of BHB (1.1) in vivo via transgenic mouse models and (1.2) in vitro via orthogonal validation of candidate pathways identified in neuronal tau interactomics. My K00 phase (Aim 2) will expand to AAs, specifically looking at isoleucine (Ile) restriction and dissecting the effects of Ile on protein synthesis (2.1), signaling (2.2), and metabolism (2.3) in the context of AD and brain aging. The unifying goal of this F99/K00 proposal is to use the KD as a starting point for the development of novel metabolic therapies for AD and brain aging by (1) identifying the bioactive components of the KD that are necessary and sufficient for its benefits in AD and brain aging and (2) disentangling the convergent and divergent mechanisms of action of dietary metabolites in AD and brain aging. This F99/K00 proposal will enable my long-term goal of establishing an independent lab that applies pharmacological, genetic, and mass spectrometry approaches to dissect the molecular underpinnings of metabolic interventions in AD and brain aging.