Title : Activation of longevity protein SIRT3 as a therapeutic strategy for Alzheimer's disease
Abstract:
Approximately 6.9 million Americans are living with Alzheimer’s disease (AD), and by 2050, this number is projected to reach nearly 13 million. A significant number of people with AD have coexisting pathologies caused by diseases including, diabetes, hypertension, and cardiovascular disease. The precondition for these comorbidities is metabolic syndrome (MetS), which is caused by the deficiency of Sirt3, a mitochondrial deacetylase. We have shown that Sirt3 gene deletion in an AD mouse leads to exacerbation of β amyloid plaque deposition, and neuroinflammation. Our hypothesis is that SIRT3 is a potential therapeutic target for the treatment of AD, especially with comorbidities. In the current study, we evaluated the efficacy of Sirt3 activator honokiol and its analogs (DCA & Hexa) in microglial cells and mouse brain. Honokiol hexafluoro (Hexa) showed maximum increase in Sirt3 levels and decrease in lysine acetylation of mitochondrial proteins, a marker for their activation, and improved mitochondrial respiration in mouse microglial cells. Next, feeding of Hexa in C57/BL6 mice showed significant increase in the SIRT3 protein levels as compared to control mice. Interestingly, BACE1, an enzyme that generates Aβ from APP decreased significantly, whereas mitochondrial fusion proteins (Mfn1 & Mfn2) and transcription factor TFAM increased in Hexa-treated mice. Importantly, Hexa treated Sirt3-/- mice showed no significant changes in BACE1, Mfn1, Mfn2, and TFAM expression, suggesting that Hexa effects are mediated by SIRT3. Finally, Hexa decreased pan acetylation in isolated primary microglia of wild type mice but not in Sirt3-/- mice. We conclude that Hexa actions are through induction of Sirt3 expression. Together, our findings demonstrate the strong potential of Hexa as a novel therapeutic agent against AD.
