Nutrient Sensor Modulators as Therapeutics for Alzheimer's disease -- Year 2

Nutrient Sensor Modulators as Therapeutics for Alzheimer’s disease Abstract To date only one disease modifying therapy for Alzheimer’s disease (AD) has been approved targeting amyloid however treatment modalities for other phenotypes and hallmarks such as tau remain unmet in the clinic. Dysregulation of brain metabolism increases with age and chronic conditions. Nutrient-sensing and amino acid signaling impact proteostasis but remain largely ignored as a therapy. Nutrient-sensing dysfunction and uncoupling of amino acid signaling has emerged as a novel entry point for targeted therapies associated with mechanistic target of rapamycin complex 1 (mTORC1). Arginine metabolism/ signaling impacts multiple biological processes that impact tau biology. Recent work showed that lysosomal and cytoplasmic arginine sensors modulate mTORC1 activity. GPRC6a is a G-protein coupled receptor that binds Lα-amino acids including arginine and may serve as an extracellular arginine sensor. Our central hypothesis suggest that tauopathies promotes uncoupling and arginine-sensing dysfunction in AD. Increased extracellular arginine signals “amino acid abundance” through GPRC6a and promotes hyper-mTORC1 activation, which slows autophagy flux and tau clearance. Allosteric antagonism or genetic repression of GPRC6a reduces receptor efficacy signaling “amino acid deficiency” to increase autophagy and tau clearance. We posit that our novel allosteric GPRC6a antagonist decreases arginine signaling to improve lysosomal function, reduce mTORC1 signaling, activate autophagy and increase tau and amyloid clearance. In aim 1, we will test how selective GPRC6a antagonists impacts the tau phenotype in two different mouse models of tauopathy harboring either wild-type tau or P301S mutations. In aim 2 we will test how this selective GPRC6a antagonist impacts a double knock-in model harboring both human APP and wildtype tau and their phenotypes. We will test how GPRC6a antagonism impacts single cell transcriptome signatures associated with mTOR, senescence, neurotransmitter function, and proteotoxic stress. This application establishes “the first new class” of GPRC6a compounds and a “new therapeutic target” for AD.