Gene and transcriptional profiles in aging mice for Sirtuin 3 haploinsufficiency Alzheimers disease model

National Institute On Aging

Investigators

Abstract

Alzheimers Disease (AD) is a neurodegenerative disorder that initially manifests as mild cognitive impairment and progresses to severe cognitive dysfunction. The pathological hallmarks of AD are characterized by the presence of amyloid-beta (A) plaques, neurofibrillary tangles, gradual loss of neuronal synapse, and memory loss. Functional brain imaging studies in human has shown that neuronal network hyperexcitability (NNH) occurs in vulnerable brain regions early in the disease progression before the cognitive impairment becomes evident. Sirtuin3 (SIRT3) is a NAD+ dependent deacetylase which removes the acetyl group from the Lysine residue of mitochondrial proteins that are involved in response to oxidative stress. SIRT3 haploinsufficiency aggravates loss of GABAergic interneurons and NNH in mouse model of AD. We previously discovered a novel role of SIRT3 in protecting neurons against excitotoxic and metabolic stress by mechanisms involving enhanced removal of mitochondrial superoxide and inhibition of apoptosis. More recently, we showed that reduced levels of SIRT3 causes significant loss of cerebral cortical interneurons and aggravates neuronal circuit hyperexcitability using SIRT3 haploinsufficient AppPs1 mutant (Sirt3+/AppPs1 or sirt3 AD mice) transgenic AD mice. These results underscore the critical role of SIRT3 in sustaining mitochondria function by mediating interneuron survival and associated neuronal network activity. In this proposal, we aim to explore the molecular mechanisms underlying neuronal hyperexcitability and premature death by investigating the transcriptomic profile using direct RNA sequencing of vulnerable brain regions of Sirt3+/AppPs1 transgenic mice. Specifically, we plan to a) identify the temporal gene expression program in the cortex of Sirt3 AD mice b) dissect the effect of Sirt3+/--mediated deregulation of Reactive Oxygen Species metabolism, RNA oxidation and decay c) identify the spatial distribution of Sirt3+/--mediated transcriptional changes in the mouse brain. To address these objectives, we have mice aging, perform direct sequencing of RNA extracted from the cortex and analyze the produced sequencing data computationally.