P1‐244: THE EFFECT OF SIRTUIN 3 ON TAU ACETYLATION IN ALZHEIMER'S DISEASE

Amyloid plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks that define AD. It is thought that neocortical Aβ triggers neocortical tau pathology. Sirt3 is down regulated in post mortem AD neocortex compared to cognitively normal (CN) subjects. Our previous study found that Sirtuin 3 (Sirt3) mediated a neuroprotective effect after brain ischemic injury by regulating oxidative stress and energy metabolism, which are involved in the pathogenesis of Alzheimer's disease (AD). However, it is unclear whether Sirt3 is associated with cognitive performance and pathological changes in AD, and the role of Sirt3 in tau pathology. We conducted a case-control study of the brains of late-onset AD, mild cognitive impairment and age matched CN subjects. We investigated Sirt3 expression, its association with cognitive performance and AD pathology.Sirt3 levels in brain tissues were quantified using sandwich enzyme linked immunosorbent assay (ELISA). In vitro, under Sir3 overexpression or knockdown condition in primary neurons, total tau and acetylated tau were evaluated with or without Aβ treatment. In total, 16 AD, 13 MCI and 11 CN subjects were enrolled in the study. Sirt3 levels (mRNA and protein expression) were significantly down-regulated in multiple areas of AD subjects compared to CN. This reduction was associated with poorer cognitive scores and neurofibrillary tangles. In vitro, overexpressed Sirt3 significantly reduced the level of tau protein, specially acetylated tau which was induced by Aβ in primary neurons. In this study, we investigated the expression and role of Sirt3 in AD, which will provide a foundation for Sirt3 as a potential disease modifying therapy. This study suggests that Sirt3 may be a potential target in tau pathology of AD. Attention to modulate Sirt3 is worth further experiment in order to provide a new insight on pathogenesis and treatment of AD. Study Supported: This work is funded by Arizona Alzheimer's Disease Consortium, Barrow Neurological Foundation (3032226) and the National Science Foundation of China (81671050); the Alzheimer Association (NIRG 14-322078).