Targeting Brain ApoE Receptors for the Treatment of Alzheimer's Disease
We aim to elucidate the mechanisms of how ApoE receptors modulate ApoE4 actions in tau pathology and to explore the therapeutic potential of targeting ApoE receptors for the treatment of AD. We propose to test the hypothesis that reduction of brain IDOL ameliorates ApoE4-mediated tau pathology and tau-associated neurodegeneration through dual mechanisms: 1) by facilitating LDLR-mediated ApoE4 clearance in the brain in Aim 1; and 2) by enhancing ApoER2-mediated signaling in neurons to inhibit tau phosphorylation and promote neuronal survival in Aim 2.
The functional interactions between ApoE receptors and ApoE4 had been shown to impact tau pathology and neurodegeneration in AD, and targeting brain ApoE receptors has long been proposed as a therapeutic strategy to combat AD. We recently showed that IDOL is a novel post-translational regulator of brain ApoE receptors, and reducing brain IDOL levels led to beneficial effects in mouse models of AD. Our results suggested IDOL may serve as a new therapeutic target for the treatment of AD. If our hypothesis in this proposal is right, then our results will validate IDOL as a new therapeutic target for the treatment of AD, and pave the way for the development of IDOL inhibitor as a novel AD-modifying medication.