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Amyloid-β Increases Tau by Mediating Sirtuin 3 in Alzheimer’s Disease

  • Junxiang Yin
  • Pengcheng Han
  • Melissa Song
  • Megan Nielsen
  • Thomas G. Beach
  • Geidy E. Serrano
  • Winnie S. Liang
  • Richard J. Caselli
  • Jiong Shi
Article

Abstract

Increasing evidence indicates that sirtuin 3 (Sirt3) has neuroprotective effects in regulating oxidative stress and energy metabolism, both of 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. We conducted a case-control study of the postmortem brains of AD (n = 16), mild cognitive impairment (n = 13), and age- and education-matched cognitively normal (CN, n = 11) subjects. We measured the mRNA and protein levels of Sirt3 and assessed their association with cognitive performance and AD pathology. In an ex vivo model of cortical neurons from transgenic mice that carry human tau protein, we modified Sirt3 expression by genetic knockdown and knock-in to investigate the cause-effect relationship between Sirt3 and tau. Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN. This reduction was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. Further study with genetic manipulation of Sirt3 revealed that amyloid-β increased levels of total tau acetylated tau through its modulation of Sirt3. These data suggest that reduction of Sirt3 is critically involved in pathogenesis of AD.

Keywords

Alzheimer’s disease Mild cognitive impairment Sirtuin Acetylation Tau Amyloid 

Notes

Acknowledgements

The authors are deeply grateful for the subjects and families who have participated in our brain donation program.

Funding Information

This work is funded by the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson’s Disease Consortium), and Barrow Neurological Foundation (3032226); the National Science Foundation of China (81671050 to JS) and the Alzheimer Association (NIRG 14-322078). The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the Michael J. Fox Foundation for Parkinson’s Research.

Compliance with Ethical Standards

The operations of the Arizona Alzheimer’s Disease Core Center and Banner Sun Health Research Institute Brain and Body Donation Program are approved by their individual Institutional Review Boards. We thus received approval for any experiments using human subjects. Written informed consent was obtained from all subjects (or guardians of subjects) participating in the study [43, 44].

Supplementary material

12035_2018_977_MOESM1_ESM.pptx (117 kb)
Supplemental Figure 1. Correlation of Sirt3 data. Sirt3 ELISA data were correlated with its western blot in MTG. (a) A representative Western blot of Sirt3 and β-actin was shown from CN, MCI and AD cases. (b) A linear correlation was depicted between Sirt3 ELISA and its Western blot (Pearson correlation r = 0.583, p = 0.011). Sirt3 of MTG was further correlated with synaptic loss on Western blot. (c) A representative Western blot of Synapsin 1 from CN, MCI and AD cases. (d) The ratios of Sirt3 and Synapsin 1 in three groups were graphed. (PPTX 117 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Barrow Neurological InstituteSt. Joseph Hospital and Medical CenterPhoenixUSA
  2. 2.School of Arts and SciencesUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Civin Laboratory for NeuropathologyBanner Sun Health Research InstituteSun CityUSA
  4. 4.Translational Genomics Research Institute (TGen)PhoenixUSA
  5. 5.Department of Neurology, Mayo Clinic ArizonaScottsdaleUSA
  6. 6.Tianjin Neurological InstituteTianjin Medical University General HospitalTianjinChina
  7. 7.Department of NeurologyBeijing Tiantan Hospital, Capital Medical UniversityBeijingChina

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