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.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder resulting in cognitive impairment and progressive dementia, and currently no effective cure has been identified. The aggregation of hyperphosphorylated tau is a pathological hallmark of AD, and thought to be the main driver for neurodegeneration in AD. Recent evidence emerged from studies of AD patients and animal models showed Apolipoprotein E4 (ApoE4) markedly exacerbates tau pathology and tau-mediated neurodegeneration in AD. Therefore, targeting ApoE4’s detrimental effects in tau pathology might serve as a promising strategy for the treatment of AD. We previously showed that a novel E3 ubiquitin ligase IDOL is a major regulator of brain ApoE receptor expression, and has a profound impact on ApoE metabolism. Our proposed studies aim to understand the multifactorial role and underlying mechanisms of action of IDOL in mitigating ApoE4-mediated tau pathology in AD. This research will have the potential to reveal a novel therapeutic target for the treatment of Alzheimer’s diseases.

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.