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

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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.

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References

  1. Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC et al (2009) Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30:1026–1036

    Article  Google Scholar 

  2. Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994) Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb Cortex 4:138–150

    Article  CAS  Google Scholar 

  3. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381

    Article  Google Scholar 

  4. Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, Beyreuther K, Masters CL (1988) A4 amyloid protein deposition and the diagnosis of Alzheimer’s disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38:1688–1693

    Article  CAS  Google Scholar 

  5. Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P et al (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216

    Article  CAS  Google Scholar 

  6. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    Article  Google Scholar 

  7. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  Google Scholar 

  8. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189

    Article  Google Scholar 

  9. Yang W, Zou Y, Zhang M, Zhao N, Tian Q, Gu M, Liu W, Shi R et al (2015) Mitochondrial Sirt3 expression is decreased in APP/PS1 double transgenic mouse model of Alzheimer’s disease. Neurochem Res 40:1576–1582

    Article  CAS  Google Scholar 

  10. Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS et al (2015) Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21:1154–1162

    Article  CAS  Google Scholar 

  11. Tracy TE, Sohn PD, Minami SS, Wang C, Min SW, Li Y, Zhou Y, Le D et al (2016) Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90:245–260

    Article  CAS  Google Scholar 

  12. Lutz MI, Milenkovic I, Regelsberger G, Kovacs GG (2014) Distinct patterns of sirtuin expression during progression of Alzheimer’s disease. NeuroMolecular Med 16:405–414

    Article  CAS  Google Scholar 

  13. Han P, Tang Z, Yin J, Maalouf M, Beach TG, Reiman EM, Shi J (2014) Pituitary adenylate cyclase-activating polypeptide protects against beta-amyloid toxicity. Neurobiol Aging 35:2064–2071

    Article  CAS  Google Scholar 

  14. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Backman L et al (2004) Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 256:240–246

    Article  CAS  Google Scholar 

  15. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269

    Article  Google Scholar 

  16. Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K, Caselli RJ, Kukull WA et al (2008) Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set. Physiol Genomics 33:240–256

    Article  CAS  Google Scholar 

  17. Jin L, Galonek H, Israelian K, Choy W, Morrison M, Xia Y, Wang X, Xu Y et al (2009) Biochemical characterization, localization, and tissue distribution of the longer form of mouse SIRT3. Protein Sci 18:514–525

    Article  CAS  Google Scholar 

  18. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590

    Article  CAS  Google Scholar 

  19. Rinetti GV, Schweizer FE (2010) Ubiquitination acutely regulates presynaptic neurotransmitter release in mammalian neurons. J Neurosci 30:3157–3166

    Article  CAS  Google Scholar 

  20. Yin JX, Maalouf M, Han P, Zhao M, Gao M, Dharshaun T, Ryan C, Whitelegge J et al (2016) Ketones block amyloid entry and improve cognition in an Alzheimer’s model. Neurobiol Aging 39:25–37

    Article  CAS  Google Scholar 

  21. Ottowitz WE, Dougherty DD, Savage CR (2002) The neural network basis for abnormalities of attention and executive function in major depressive disorder: implications for application of the medical disease model to psychiatric disorders. Harv Rev Psychiatry 10:86–99

    Article  Google Scholar 

  22. Obler LK, Rykhlevskaia E, Schnyer D, Clark-Cotton MR, Spiro A 3rd, Hyun J, Kim DS, Goral M et al (2010) Bilateral brain regions associated with naming in older adults. Brain Lang 113:113–123

    Article  Google Scholar 

  23. Kincaid B, Bossy-Wetzel E (2013) Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci 5:48

    Article  Google Scholar 

  24. McDonnell E, Peterson BS, Bomze HM, Hirschey MD (2015) SIRT3 regulates progression and development of diseases of aging. Trends Endocrinol Metab 26:486–492

    Article  CAS  Google Scholar 

  25. Vishnu VY (2013) Can tauopathy shake the amyloid cascade hypothesis? Nat Rev Neurol 9:356

    Article  Google Scholar 

  26. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128

    Article  CAS  Google Scholar 

  27. Landau SM, Frosch MP (2014) Tracking the earliest pathologic changes in Alzheimer disease. Neurology 82:1576–1577

    Article  Google Scholar 

  28. Attems J, Jellinger KA (2013) Amyloid and tau: neither chicken nor egg but two partners in crime! Acta Neuropathol 126:619–621

    Article  Google Scholar 

  29. Mann DM, Hardy J (2013) Amyloid or tau: the chicken or the egg? Acta Neuropathol 126:609–613

    Article  Google Scholar 

  30. Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181

    Article  Google Scholar 

  31. Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC (2015) Tau imaging: early progress and future directions. Lancet Neurol 14:114–124

    Article  Google Scholar 

  32. Chetelat G (2013) Alzheimer disease: Abeta-independent processes-rethinking preclinical AD. Nat Rev Neurol 9:123–124

    Article  CAS  Google Scholar 

  33. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Sarmiento J, Troncoso J, Jackson GR, Kayed R (2012) Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J 26:1946–1959

    Article  CAS  Google Scholar 

  34. Ren Y, Sahara N (2013) Characteristics of tau oligomers. Front Neurol 4:102

    Article  Google Scholar 

  35. Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, Lee VM (2011) The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun 2:252

    Article  Google Scholar 

  36. Sanz A, Hiona A, Kujoth GC, Seo AY, Hofer T, Kouwenhoven E, Kalani R, Prolla TA et al (2007) Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice. Exp Gerontol 42:173–182

    Article  CAS  Google Scholar 

  37. Vina J, Borras C (2010) Women live longer than men: understanding molecular mechanisms offers opportunities to intervene by using estrogenic compounds. Antioxid Redox Signal 13:269–278

    Article  CAS  Google Scholar 

  38. Germain D (2016) Sirtuins and the estrogen receptor as regulators of the mammalian mitochondrial UPR in cancer and aging. Adv Cancer Res 130:211–256

    Article  CAS  Google Scholar 

  39. Singh P, Hanson PS, Morris CM (2017) SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson’s disease. BMC Neurosci 18:46

    Article  Google Scholar 

  40. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA et al (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179

    Article  CAS  Google Scholar 

  41. Braidy N, Jayasena T, Poljak A, Sachdev PS (2012) Sirtuins in cognitive ageing and Alzheimer’s disease. Curr Opin Psychiatry 25:226–230

    Article  Google Scholar 

  42. Yin J, Han P, Tang Z, Liu Q, Shi J (2015) Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. J Cereb Blood Flow Metab 35:1783–1789

    Article  CAS  Google Scholar 

  43. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, Lue L, Roher AE et al (2015) Arizona study of aging and neurodegenerative disorders and brain and body donation program. Neuropathology 35:354–389

    Article  Google Scholar 

  44. Han P, Liang W, Baxter LC, Yin J, Tang Z, Beach TG, Caselli RJ, Reiman EM et al (2014) Pituitary adenylate cyclase-activating polypeptide is reduced in Alzheimer disease. Neurology 82:1724–1728

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Funding

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.

Author information

Authors and Affiliations

  1. Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Phoenix, AZ, USA

    Junxiang Yin, Pengcheng Han, Melissa Song, Megan Nielsen & Jiong Shi

  2. School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA

    Melissa Song

  3. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA

    Thomas G. Beach & Geidy E. Serrano

  4. Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

    Winnie S. Liang

  5. Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA

    Richard J. Caselli

  6. Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China

    Jiong Shi

  7. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Jiong Shi

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  1. Junxiang Yin
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  2. Pengcheng Han
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Correspondence to Jiong Shi.

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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].

Electronic Supplementary Material

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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Yin, J., Han, P., Song, M. et al. Amyloid-β Increases Tau by Mediating Sirtuin 3 in Alzheimer’s Disease. Mol Neurobiol 55, 8592–8601 (2018). https://doi.org/10.1007/s12035-018-0977-0

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  • DOI: https://doi.org/10.1007/s12035-018-0977-0

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