Advertisement

Neuroscience Bulletin

, Volume 34, Issue 6, pp 1127–1130 | Cite as

The Mitochondrion: A Potential Therapeutic Target for Alzheimer’s Disease

  • Mei-Hong Lu
  • Xiu-Yun Zhao
  • Pei-Pei Yao
  • De-En Xu
  • Quan-Hong MaEmail author
Perspective

Introduction

The mitochondrion is a double-membrane organelle consisting of an outer membrane, intermembrane space, inner membrane, cristae, and matrix. It is the “energy plant” that provides most of the energy for cells. Mitochondria also participate in various processes such as calcium homeostasis, cell death, and cell growth during development and aging [1]. Mitochondrial abnormalities are a common phenomenon in aging and age-related neurodegenerative diseases such as Alzheimer’s disease (AD). Mitochondrial dysfunction is even taken to be a marker for aging, an indispensable risk factor for AD [1]. Anti-oxidants and factors that maintain mitochondrial homeostasis have beneficial effects in AD therapy. Thus, the mitochondrion is emerging as a novel target for AD therapy.

Mitochondrial Dysfunction is an Early and Common Feature of AD

AD is a neurodegenerative disease characterized by deficits in learning, memory, and other cognitive functions. Its major pathological characteristics...

Notes

Acknowledgements

This perspective article was supported by the National Natural Science Foundation of China (81870897, 81671111, and 81601111), the Natural Science Foundation of Jiangsu Province, China (BK20181436), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Suzhou Clinical Research Center of Neurological Disease (Szzx201503), a Jiangsu Provincial Medical Key Discipline Project (ZDXKB2016022), the Jiangsu Provincial Special Program of Medical Science (BL2014042), and the Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases (BM2013003).

Conflict of interest

The authors have no conflicting financial interests.

References

  1. 1.
    Srivastava S. The mitochondrial basis of aging and age-related disorders. Genes (Basel) 2017, 8.Google Scholar
  2. 2.
    Zhu Y, Zhang H. A mouse model of Alzheimer’s disease with transplanted stem-cell-derived human neurons. Neurosci Bull 2017, 33: 766–768.CrossRefGoogle Scholar
  3. 3.
    Yang A, Wang C, Song B, Zhang W, Guo Y, Yang R, et al. Attenuation of beta-amyloid toxicity in vitro and in vivo by accelerated aggregation. Neurosci Bull 2017, 33: 405–412.CrossRefGoogle Scholar
  4. 4.
    Yu Y, Li Y, Zhang Y. Yeast two-hybrid screening for proteins that interact with the extracellular domain of amyloid precursor protein. Neurosci Bull 2016, 32: 171–176.CrossRefGoogle Scholar
  5. 5.
    Hu Y, Li XC, Wang ZH, Luo Y, Zhang X, Liu XP, et al. Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin. Oncotarget 2016, 7: 17356–17368.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Li XC, Hu Y, Wang ZH, Luo Y, Zhang Y, Liu XP, et al. Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Sci Rep 2016, 6: 24756.CrossRefGoogle Scholar
  7. 7.
    Swerdlow RH, Burns JM, Khan SM. The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta 2014, 1842: 1219–1231.CrossRefGoogle Scholar
  8. 8.
    Pickett EK, Rose J, McCrory C, McKenzie CA, King D, Smith C, et al. Region-specific depletion of synaptic mitochondria in the brains of patients with Alzheimer’s disease. Acta Neuropathol 2018, 136: 747–757.CrossRefGoogle Scholar
  9. 9.
    Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev 2013, 2013: 316523.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Ansari MA, Scheff SW. Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 2010, 69: 155–167.CrossRefGoogle Scholar
  11. 11.
    Mecocci P, Polidori MC. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim Biophys Acta 2012, 1822: 631–638.CrossRefGoogle Scholar
  12. 12.
    Schmidt C, Lepsverdize E, Chi SL, Das AM, Pizzo SV, Dityatev A, et al. Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Mol Psychiatry 2008, 13: 953–969.CrossRefGoogle Scholar
  13. 13.
    Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, Strosznajder JB, et al. Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 2004, 279: 50310–50320.CrossRefGoogle Scholar
  14. 14.
    Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, et al. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 2009, 324: 102–105.CrossRefGoogle Scholar
  15. 15.
    Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 2004, 304: 448–452.CrossRefGoogle Scholar
  16. 16.
    Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res 2016, 1643: 1–9.CrossRefGoogle Scholar
  17. 17.
    Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, et al. NAD(+) supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 2018, 115: E1876–E1885.CrossRefGoogle Scholar
  18. 18.
    David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 2005, 280: 23802–23814.CrossRefGoogle Scholar
  19. 19.
    Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA, et al. Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms. Trends Neurosci 2017, 40: 151–166.CrossRefGoogle Scholar
  20. 20.
    Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010, 141: 1146–1158.CrossRefGoogle Scholar
  21. 21.
    Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA. Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 2016, 17: 308–321.CrossRefGoogle Scholar
  22. 22.
    Julien C, Tremblay C, Emond V, Lebbadi M, Salem N, Jr., Bennett DA, et al. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 2009, 68: 48–58.CrossRefGoogle Scholar
  23. 23.
    Tseng AH, Shieh SS, Wang DL. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med 2013, 63: 222–234.CrossRefGoogle Scholar
  24. 24.
    Yang W, Zou Y, Zhang M, Zhao N, Tian Q, Gu M, et al. Mitochondrial Sirt3 expression is decreased in APP/PS1 double transgenic mouse model of Alzheimer’s disease. Neurochem Res 2015, 40: 1576–1582.CrossRefGoogle Scholar
  25. 25.
    Salminen A, Kaarniranta K, Kauppinen A, Ojala J, Haapasalo A, Soininen H, et al. Impaired autophagy and APP processing in Alzheimer’s disease: The potential role of Beclin 1 interactome. Prog Neurobiol 2013, 106-107: 33–54.CrossRefGoogle Scholar
  26. 26.
    Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ, et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 2013, 12: 370–380.CrossRefGoogle Scholar
  27. 27.
    Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 2010, 5: e9979.CrossRefGoogle Scholar
  28. 28.
    Du J, Liang Y, Xu F, Sun B, Wang Z. Trehalose rescues Alzheimer’s disease phenotypes in APP/PS1 transgenic mice. J Pharm Pharmacol 2013, 65: 1753–1756.CrossRefGoogle Scholar
  29. 29.
    Portbury SD, Hare DJ, Sgambelloni C, Perronnes K, Portbury AJ, Finkelstein DI, et al. Trehalose improves cognition in the transgenic Tg2576 mouse model of Alzheimer’s disease. J Alzheimers Dis 2017, 60: 549–560.CrossRefGoogle Scholar
  30. 30.
    Wang Z, Lu M, Zhang Y, Ji W, Lei L, Wang W, et al. DISC1 protects synaptic plasticity in a transgenic mouse model of Alzheimer’s disease as a mitophagy receptor. Aging Cell 2018.Google Scholar
  31. 31.
    Deng QS, Dong XY, Wu H, Wang W, Wang ZT, Zhu JW, et al. Disrupted-in-schizophrenia-1 attenuates amyloid-beta generation and cognitive deficits in APP/PS1 transgenic mice by reduction of beta-site APP-cleaving enzyme 1 Levels. Neuropsychopharmacology 2016, 41: 440–453.CrossRefGoogle Scholar
  32. 32.
    Shen L, Jia J. An overview of genome-wide association studies in Alzheimer’s disease. Neurosci Bull 2016, 32: 183–190.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Mei-Hong Lu
    • 1
    • 2
  • Xiu-Yun Zhao
    • 1
    • 2
  • Pei-Pei Yao
    • 1
    • 2
  • De-En Xu
    • 3
  • Quan-Hong Ma
    • 1
    • 2
    Email author
  1. 1.Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouChina
  2. 2.Department of Neurology and Suzhou Clinical Research Center of Neurological DiseaseThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
  3. 3.Wuxi No. 2 People’s HospitalWuxiChina

Personalised recommendations