Activation of SIRT3 as a Therapeutic Strategy for Alzheimer's Disease

Va Eastern Colorado Health Care System, Aurora CO

Investigators

Linked publications & trials

Abstract

Background and Innovation: Alzheimer’s disease (AD) affects 10-15% of people after the age of 65. Around 50% of 21 million veterans, now in this age group, are disproportionately at a higher risk of developing AD. Majority of veterans with AD have coexisting pathologies caused by diseases including, diabetes, hypertension, and cardiovascular disease. Metabolic syndrome (MetS) is the precondition for these comorbidities. Mitochondrial proteins are hyperacetylated in MetS leading to their decreased function. These protein modifications are reversed by the deacetylase enzyme, known as SIRT3, the focus of this study. Studies on SIRT3 function have generally remained in the domain of peripheral tissues. Our lab has made a significant contribution to the understanding of SIRT3-regulated brain mitochondrial function with a series of key publications. First, we observed brain mitochondrial dysfunction and inflammasome formation, a trigger for the neuroinflammatory pathway in Sirt3-/- mice. Next, we generated APP/PS1/Sirt3-/- mice as a novel comorbid mouse model with amyloid pathology and MetS. We observed in these mice that SIRT3 deficiency exacerbates brain insulin resistance, neuroinflammation, amyloid plaque deposition and astrogliosis. Later, by RNA seq analysis of brain samples, we demonstrated that the expression of insulin degrading enzyme (IDE), involved in the regulation of insulin as well as degradation of Aβ, is decreased by ~50% following Sirt3 gene deletion. Furthermore, by activation of SIRT3 with nicotinamide riboside in vivo and in vitro, we observed increases the levels of IDE and neprilysin, another Aβ degrading enzyme and decreased the expression of BACE1, a key regulatory enzyme in the generation of Aβ. Thus, targeting SIRT3 in AD is novel and innovative because of its actions on key regulatory pathways where MetS and amyloid pathology interact. Significance and Impact to Veterans Healthcare: Our findings suggest that not only SIRT3 activation prevents the actions of MetS in the exacerbation of AD pathogenesis, but also directly ameliorate multiple pathologies in the Alzheimer’s brain. Therefore, the central goal of current research project is to use genetic and pharmacological approaches to test the effects of SIRT3 activation in Alzheimer’s mouse model and in cultured primary microglia. Our recent studies have moved us further in this direction. First, we generated successfully Sirt3 overexpressing mice in C57/BL6 background by a Cre-Lox system and observed upregulation of IDE in the brain. In a parallel collaborative study, we tested the effects of a new class of potential drug molecules for the treatment of AD, namely DCA and Hexa, synthetic analogs of honokiol, a naturally occurring SIRT3 activator. These analogs have been characterized for their improved lipophilicity, bioavailability, and stability by our collaborator, Dr. Arbiser (Emory University, Atlanta, GA). Based on our preliminary studies, we chose Hexa as the most potent drug molecule for further investigation. Hexa improved mitochondrial respiration and decreased neuroinflammation in in vivo and in cultured mouse primary microglia in a SIRT3 dependent manner. Our proposed research is relevant and significant to the health care of Veterans. Therefore, outcomes of the proposed proposal will contribute to the development of strategies to treat AD which is prevalent among veteran population. Path to translation/implementation: Herein, we will test the hypothesis that “SIRT3 has the potential to ameliorate multiple key pathways of Alzheimer’s disease” with the following Specific Aims. Aim 1: To test the efficacy of SIRT3 activator Hexa in decreasing Alzheimer’s pathologies in APP/PS1 mice. Aim 2: To determine the effects of Sirt3 overexpression on brain transcriptome, metabolism, and insulin signaling in APP/PS1 mice. Aim3: To determine how SIRT3 activation leads to improvement in microglial function. The potential outcome of our proposed plan is that a novel pathway will be identified as a therapeutic strategy for AD treatment which will have significant impact on veterans’ healthcare.