Alterations in Mitochondrial Dynamic-related Genes in the Peripheral Blood of Alzheimer’s Disease Patients

Author(s): Nattaporn Pakpian, Kamonrat Phopin, Kuntida Kitidee, Piyarat Govitrapong, Prapimpun Wongchitrat*

Journal Name: Current Alzheimer Research

Volume 17 , Issue 7 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: Mitochondrial dysfunction is a pathological feature that manifests early in the brains of patients with Alzheimer’s Disease (AD). The disruption of mitochondrial dynamics contributes to mitochondrial morphological and functional impairments. Our previous study demonstrated that the expression of genes involved in amyloid beta generation was altered in the peripheral blood of AD patients.

Objective: The aim of this study was to further investigate the relative levels of mitochondrial genes involved in mitochondrial dynamics, including mitochondrial fission and fusion, and mitophagy in peripheral blood samples from patients with AD compared to healthy controls.

Methods: The mRNA levels were analyzed by real-time polymerase chain reaction. Gene expression profiles were assessed in relation to cognitive performance.

Results: Significant changes were observed in the mRNA expression levels of fission-related genes; Fission1 (FIS1) levels in AD subjects were significantly higher than those in healthy controls, whereas Dynamin- related protein 1 (DRP1) expression was significantly lower in AD subjects. The levels of the mitophagy-related genes, PTEN-induced kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3), were significantly increased in AD subjects and elderly controls compared to healthy young controls. The mRNA levels of Parkin (PARK2) were significantly decreased in AD. Correlations were found between the expression levels of FIS1, DRP1 and PARK2 and cognitive performance scores.

Conclusion: Alterations in mitochondrial dynamics in the blood may reflect impairments in mitochondrial functions in the central and peripheral tissues of AD patients. Mitochondrial fission, together with mitophagy gene profiles, might be potential considerations for the future development of blood-based biomarkers for AD.

Keywords: Alzheimer's disease, mitochondrial dynamics, mitophagy, FIS1, DRP1, aging.

GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390(10100): 1151-210.
[] [PMID: 28919116]
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82(4): 239-59.
[] [PMID: 1759558]
Cai Q, Tammineni P. Alterations in mitochondrial quality control in Alzheimer’s disease. Front Cell Neurosci 2016; 10: 24.
[] [PMID: 26903809]
Leuner K, Schulz K, Schütt T, et al. Peripheral mitochondrial dysfunction in Alzheimer’s disease: Focus on lymphocytes. Mol Neurobiol 2012; 46(1): 194-204.
[] [PMID: 22821186]
Zhu X, Perry G, Moreira PI, et al. Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J Alzheimers Dis 2006; 9(2): 147-53.
[] [PMID: 16873962]
Blass JP, Gibson GE. The role of oxidative abnormalities in the pathophysiology of Alzheimer’s disease. Rev Neurol (Paris) 1991; 147(6-7): 513-25.
[PMID: 1962057]
Lejri I, Agapouda A, Grimm A, Eckert A. Mitochondria- and oxidative stress-targeting substances in cognitive decline-related disorders: From molecular mechanisms to clinical evidence. Oxid Med Cell Longev 2019; 20199695412
[] [PMID: 31214285]
Caspersen C, Wang N, Yao J, et al. Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J 2005; 19(14): 2040-1.
[] [PMID: 16210396]
Swerdlow RH. Mitochondria and mitochondrial cascades in Alzheimer’s disease. J Alzheimers Dis 2018; 62(3): 1403-16.
[] [PMID: 29036828]
Lee H, Yoon Y. Mitochondrial fission and fusion. Biochem Soc Trans 2016; 44(6): 1725-35.
[] [PMID: 27913683]
Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol 2020; 21(4): 204-24.
[] [PMID: 32071438]
Santel A, Fuller MT. Control of mitochondrial morphology by a human mitofusin. J Cell Sci 2001; 114(Pt 5): 867-74.
[PMID: 11181170]
Losón OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 2013; 24(5): 659-67.
[] [PMID: 23283981]
Martinez-Vicente M. Neuronal mitophagy in neurodegenerative diseases. Front Mol Neurosci 2017; 10: 64.
[] [PMID: 28337125]
Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 2007; 282(33): 24131-45.
[] [PMID: 17580304]
Yoo SM, Jung YK. A molecular approach to mitophagy and mitochondrial dynamics. Mol Cells 2018; 41(1): 18-26.
[PMID: 29370689]
Zhu T, Chen JL, Wang Q, Shao W, Qi B. Modulation of mitochondrial dynamics in neurodegenerative diseases: An insight into prion diseases. Front Aging Neurosci 2018; 10: 336.
[] [PMID: 30455640]
Joshi AU, Saw NL, Shamloo M, Mochly-Rosen D. Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer’s disease. Oncotarget 2017; 9(5): 6128-43.
[] [PMID: 29464060]
Manczak M, Calkins MJ, Reddy PH. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: Implications for neuronal damage. Hum Mol Genet 2011; 20(13): 2495-509.
[] [PMID: 21459773]
Wang X, Su B, Lee HG, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 2009; 29(28): 9090-103.
[] [PMID: 19605646]
Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P. Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Brain Res Rev 2011; 67(1-2): 103-18.
[] [PMID: 21145355]
Kerr JS, Adriaanse BA, Greig NH, et al. Mitophagy and Alzheimer’s disease: Cellular and molecular mechanisms. Trends Neurosci 2017; 40(3): 151-66.
[] [PMID: 28190529]
Nixon RA, Wegiel J, Kumar A, et al. Extensive involvement of autophagy in Alzheimer disease: An immuno-electron microscopy study. J Neuropathol Exp Neurol 2005; 64(2): 113-22.
[] [PMID: 15751225]
Wang X, Su B, Fujioka H, Zhu X. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 2008; 173(2): 470-82.
[] [PMID: 18599615]
Martín-Maestro P, Gargini R, Perry G, Avila J, García-Escudero V. PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer’s disease. Hum Mol Genet 2016; 25(4): 792-806.
[] [PMID: 26721933]
Flannery PJ, Trushina E. Mitochondrial dynamics and transport in Alzheimer’s disease. Mol Cell Neurosci 2019; 98: 109-20.
[] [PMID: 31216425]
Delbarba A, Abate G, Prandelli C, et al. Mitochondrial alterations in peripheral mononuclear blood cells from Alzheimer’s disease and mild cognitive impairment patients. Oxid Med Cell Longev 2016; 20165923938
[] [PMID: 26881032]
Wongchitrat P, Pakpian N, Kitidee K, Phopin K, Dharmasaroja PA, Govitrapong P. Alterations in the expression of amyloid precursor protein cleaving enzymes MRNA in Alzheimer peripheral blood. Curr Alzheimer Res 2019; 16(1): 29-38.
[] [PMID: 30411686]
Train the Brain Forum Committee Thai mental state examination (TMSE). Siriraj Med J 1993; 45(6): 359.
Muangpaisan W, Assantachai P, Sitthichai K, Richardson K, Brayne C. The distribution of thai mental state examination scores among non-demented elderly in suburban bangkok metropolitan and associated factors. J Med Assoc Thailand Chotmaihet Thangphaet 2015; 98(9): 916-24.
Senanarong V, Harnphadungkit K, Poungvarin N, et al. The dementia and disability project in Thai Elderly: Rational, design, methodology and early results. BMC Neurol 2013; 13(1): 3.
[] [PMID: 23305293]
Senanarong V, Siwasariyanon N, Washirutmangkur L, et al. Alzheimer’s disease dementia as the diagnosis best supported by the cerebrospinal fluid biomarkers: Difference in cut-off levels from thai experience. Int J Alzheimers Dis 2012; 2012212063
Chen H, Chan DC. Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet 2009; 18(R2): R169-76.
[] [PMID: 19808793]
Chan DC. Fusion and fission: Interlinked processes critical for mitochondrial health. Annu Rev Genet 2012; 46: 265-87.
[] [PMID: 22934639]
Valla J, Schneider L, Niedzielko T, et al. Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 2006; 6(6): 323-30.
[] [PMID: 17123871]
Wang S, Song J, Tan M, Albers KM, Jia J. Mitochondrial fission proteins in peripheral blood lymphocytes are potential biomarkers for Alzheimer’s disease. Eur J Neurol 2012; 19(7): 1015-22.
[] [PMID: 22340708]
Martín-Maestro P, Gargini R, García E, Perry G, Avila J, García-Escudero V. Slower dynamics and aged mitochondria in sporadic Alzheimer’s disease. Oxid Med Cell Longev 2017; 20179302761
[] [PMID: 29201274]
Koch A, Yoon Y, Bonekamp NA, McNiven MA, Schrader M. A role for Fis1 in both mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 2005; 16(11): 5077-86.
[] [PMID: 16107562]
Zhu X, Perry G, Smith MA, Wang X. Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis 2013; 33(1): S253-62.
[] [PMID: 22531428]
Wang X, Su B, Siedlak SL, et al. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 2008; 105(49): 19318-23.
[] [PMID: 19050078]
Mise A, Yoshino Y, Yamazaki K, et al. TOMM40 and APOE gene expression and cognitive decline in Japanese Alzheimer’s disease subjects. J Alzheimers Dis 2017; 60(3): 1107-17.
[] [PMID: 28984592]
Choi J, Ravipati A, Nimmagadda V, Schubert M, Castellani RJ, Russell JW. Potential roles of PINK1 for increased PGC-1α-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes. Mitochondrion 2014; 18: 41-8.
[] [PMID: 25260493]
Ye X, Sun X, Starovoytov V, Cai Q. Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer’s disease patient brains. Hum Mol Genet 2015; 24(10): 2938-51.
[] [PMID: 25678552]
François A, Julian A, Ragot S, et al. Inflammatory stress on autophagy in peripheral blood mononuclear cells from patients with Alzheimer’s disease during 24 months of follow-up. PLoS One 2015; 10(9)e0138326
[] [PMID: 26393801]
Dyer RR, Ford KI, Robinson RAS. The roles of S-nitrosylation and S-glutathionylation in Alzheimer’s disease. Methods Enzymol 2019; 626: 499-538.
[] [PMID: 31606089]
Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 2015; 85(2): 257-73.
[] [PMID: 25611507]
Fivenson EM, Lautrup S, Sun N, et al. Mitophagy in neurodegeneration and aging. Neurochem Int 2017; 109: 202-9.
[] [PMID: 28235551]
Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 2019; 22(3): 401-12.
[] [PMID: 30742114]
Fedorowicz MA, de Vries-Schneider RL, Rüb C, et al. Cytosolic cleaved PINK1 represses Parkin translocation to mitochondria and mitophagy. EMBO Rep 2014; 15(1): 86-93.
[] [PMID: 24357652]
Reddy PH, Oliver DM. Amyloid beta and phosphorylated tau-induced defective autophagy and mitophagy in Alzheimer’s disease. Cells 2019; 8(5)E488
[] [PMID: 31121890]
Chen Y, Dorn GW II. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 2013; 340(6131): 471-5.
[] [PMID: 23620051]
Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM. LC3/GABARAP family proteins: Autophagy-(un)related functions. FASEB J 2016; 30(12): 3961-78.
[] [PMID: 27601442]
Nakatogawa H. Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy. Essays Biochem 2013; 55: 39-50.
[] [PMID: 24070470]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 06 October, 2020
Page: [616 - 625]
Pages: 10
DOI: 10.2174/1567205017666201006162538
Price: $65

Article Metrics

PDF: 21