RLIP, Mitochondrial Dysfunction in Alzheimer’s Disease

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PROJECT SUMMARY Alzheimer's disease (AD) is a neurodegenerative disorder that affects a large proportion of the aging population. Despite its prevalence, no specific treatments can prevent or treat this disease. Research on the pathophysiology of the disease and the testing of new drugs is limited to transgenic mouse models harboring mutated versions of AD-related genes, including APP, PSEN1, APOEɛ4, and ob (leptin). Since oxidative stress (OS) in the brain is believed to be involved in AD pathogenesis, markers of OS such as protein oxidation, lipid oxidation, DNA oxidation, glycoxidation, and mitochondrial dysfunction may also have utility as markers for AD. RalBP1 (Rlip) is a stress-activated protein that plays a crucial role in OS defense as the rate- determining enzyme in the efflux of the GSH-conjugated oxidative metabolites. While we have extensively characterized the role of Rlip as a centrally important oxidative stress-defense mechanism in the etiologies of cancer, metabolic syndrome, and diabetes, we have only recently begun to study its function in neurons. Our preliminary data and published suggests that the Rlip knockout in neuronal cells and Rlip mice developed strong mechanistic links with oxidative stress/mitochondrial dysfunction and synaptic damage in AD. Further, Rlip deficient mice and neurons have increased OS in the brain and downregulation of NRF2, which OS normally up-regulates. This dysregulated NRF2 response likely contributes to further exacerbated oxidative stress, impaired xenobiotic metabolism, and dysregulated mitochondrial functions in these mice. We provide intriguing preliminary evidence of Rlip deficiency in human postmortem AD brains and abnormalities of mitochondrial structure, function, and proteins in Rlip deficient mice and in Rlip deficient neurons in culture. Our preliminary studies show that Rlip depletion epigenetically regulates several AD-linked genes, including CREBBP, a gene implicated in neurocognition. The Rlip+/- model will allow us to develop an oxidative stress animal model of AD, which in turn will be helpful in the development of drugs for the treatment of AD and in conducting studies that will lead to novel findings on AD biology. Based on our preliminary findings, we hypothesize that Rlip deficiency causes oxidative stress, which exacerbates neurodegeneration and dysregulation of neurocognitive functions; therefore, reducing oxidative stress signaling through Rlip upregulation may improve mitochondrial and synaptic functions and cognitive behavior. Under the proposed Aims 1) we will study whether Rlip knockout mice have neurocognitive, histopathological, biochemical, and neuronal deficits resembling those seen in humanized Aβ knock-in (hAβ-KI) mice, and 2) whether Rlip upregulation ameliorates the phenotypic severity of the hAβ-KI model. These studies will offer novel insights into the regulation of oxidative stress defenses in AD and may lead to new treatments for AD.