Aging
Navigate
Submit an Article
Research Paper|Volume 10, Issue 10|pp 2874—2883

Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism

Junxiang Yin1, Shiping Li1,2, Megan Nielsen1,3, Tanner Carcione1, Winnie S. Liang4, Jiong Shi1,5
  • 1Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ 85013, USA
  • 2Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
  • 3College of Science, University of Arizona, Tucson, AZ 85721, USA
  • 4Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
  • 5Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

* * Equal contribution

Received: August 22, 2018Accepted: October 5, 2018Published: October 23, 2018
https://doi.org/10.18632/aging.101592

Copyright: © 2018 Yin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alzheimer’s disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.