Hostname: page-component-cd9895bd7-gbm5v Total loading time: 0 Render date: 2024-12-23T16:09:42.219Z Has data issue: false hasContentIssue false
  • English
  • Français

Role of Mitochondria in Neurodegenerative Diseases: Mitochondria as a Therapeutic Target in Alzheimer's Disease

Published online by Cambridge University Press:  07 November 2014

P. Hemachandra Reddy
Get access Rights & Permissions [Opens in a new window]

Extract

A growing body of evidence suggests that mitochondrial abnormalities are involved in aging and in age-related neurodegenerative diseases as well as cancer, diabetes, and several other diseases known to be affected by mitochondria. Causal factors for most age-related neurodegenerative diseases—including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA)—are largely unknown. Genetic defects are reported to cause a small number of neurodegenerative diseases (Slide 1), but cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. However, based on several cellular, molecular, and animal model studies of Alzheimer's disease, Parkinson's disease, ALS, FRDA, cancer, and diabetes, aging may play a large role in cell death in these diseases. Age-dependent, mitochondrially-generated reactive oxygen species (ROS) have been identified as important factors responsible for disease progression and cell death, particularly in late-onset diseases, in which genetic mutations are not causal factors.

Type
Expert Panel Supplement
Information
CNS Spectrums , Volume 14 , Issue S7: Mitochondria: An Emerging Therapeutic Focus in Alzheimer's Disease Therapy , August 2009 , pp. 8 - 13
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Lin, MT, Beal, MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006; 443(7113):787–795.CrossRefGoogle ScholarPubMed
2.Reddy, PH. Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med. 2008;10(4):291–315Google Scholar
3.DiMauro, S, Schon, EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008:31:91–123.Google Scholar
4.Beal, MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. 2005;58(4):495–505.Google Scholar
5.Manczak, M, Jung, Y, Park, BS, Partovi, D, Reddy, PH. Time-course of mitochondrial gene expressions in mice brains: implications for mitochondrial dysfunction, oxidative damage, and cytochrome c in aging. JNeurochem. 2005;92(3):494–504.CrossRefGoogle ScholarPubMed
6.Swerdlow, RH, Khan, SM. A “mitochondrial cascade hypothesis” for sporadic Alzheimer's disease. Med Hypotheses. 2004:63(1):8–20.Google Scholar
7.Reddy, PH, Beal, MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008;14(2):45–53.Google Scholar
8.Reddy, PH. Mitochondrial dysfunction in aging and Alzheimer's disease: strategies to protect neurons. Antioxid Redox Signal. 2007;9(10): 1647–1658.Google Scholar
9.Anderson, S, Bankier, AT, Barrell, BG, et al.Sequence and organization of the human mitochondrial genome. Nature. 1981;290(5806):457–465.CrossRefGoogle ScholarPubMed
10.Reddy, PH, Beal, MF. Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res Brain Res Rev. 2005;49(3):618–632.CrossRefGoogle ScholarPubMed
11.Reddy, PH, Mao, P, Manczak, M.Mitochondrial structural and functional dynamics in Huntington'sdisease. Brain Res Rev. 2009:61(1):33–48.Google Scholar
12.Selkoe, DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001;81(2):741–766.Google Scholar
13.Mattson, MRPathways towards and away from Alzheimer's disease. Nature. 2004:430(7000):631–639.Google Scholar
14.Reddy, PH, McWeeney, S.Mapping cellular transcriptosomes in autopsied Alzheimer's disease subjects and relevant animal models. Neurobiol Aging. 2006;27(8):1060–1077.Google Scholar
15.Selkoe, DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298(5594):789–791.Google Scholar
16.Nunomura, A, Perry, G, Aliev, G, et al.Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001:60(8):759–767.Google Scholar
17.Reddy, PH. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease. Exp Neurol. 218(2):286–292.Google Scholar
18.Manczak, M, Anekonda, TS, Henson, E, Park, BS, Quinn, J, Reddy, PH. Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006;15(9):1437–1449.Google Scholar
19.Crouch, PJ, Blake, R, Duce, JA, et al.Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-betai-42. J Neurosci. 2005;25(3):672–679.CrossRefGoogle Scholar
20.Caspersen, C, Wang, N, Yaq, J, et al.Mitochondrial Abeta: a potential focal point for neuranal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005:19(14):2040–2041.CrossRefGoogle Scholar
21.Devi, L, Prabhu, BM, Galati, DFAvadhani, NG, Anandatheerthavarada, HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006;26(35):9057–9068.CrossRefGoogle ScholarPubMed
22.Hansson Petersen, CA, Alikhani, N, Behbahani, H, et al.The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008;105(35):13145–13150.Google Scholar
23.Anandatheerthavarada, HK, Biswas, G, Robin, MA, Avadhani, NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuranal cells. J Cell Biol. 2003;161(1):41–54.Google Scholar
24.Keil, U, Bonert, A, Marques, CA, et al.Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem. 2004;279(48):50310–50320.Google Scholar
25.Park, HJ, Kim, SS, Seong, YM, et al.Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria. J Biol Chem. 2006:281(451:34277–34287.Google Scholar
26.Gibson, GE, Sheu, KF, Blass, JP. Abnormalities of mitochondrial enzymes in Alzheimer disease. J Neural Transm. 1998;105(8–9):855–870.Google Scholar
27.Parker, WD Jr, Filley, CM, Parks, JK. Cytochrome oxidase deficiency in Alzheimer's disease. Neurology. 1990;40(8):1302–1303.Google Scholar
28.Maurer, I, Zierz, S, Möller, HJ. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging. 2000;21(3):455–462.Google Scholar
29.Smith, MA, Perry, G, Richey, PL, et al.Oxidative damage in Alzheimer's. Nature. 1996;382(6587):120–121.Google Scholar
30.Lin, MT, Simon, DK, Ahn, CH, Kim, LM, Beal, MF. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum Mol Genet. 2002;11(2):133–145.Google Scholar
31.Coskun, PE, Beal, MF, Wallace, DC. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA. 2004;101(29):10726–10731.Google Scholar
32.Chandrasekaran, K, Giordano, T, Brady, DR, Stoll, J, Martin, LJ, Rapoport, SI. Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. Brain Res Mol Brain Res. 1994;24(1–4):336–340.Google Scholar
33.Reddy, PH, McWeeney, S, Park, BS, et al.Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 2004;13(12):1225–1240.Google Scholar
34.Manczak, M, Park, BS, Jung, Y, Reddy, PH. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 2004;5(2):147–162.Google Scholar
35.Hirai, K, Aliev, G, Nunomura, A, et al.Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001;21(9):3017–3023.Google Scholar
36.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): 19318–19323.Google Scholar
37.Reddy, PH, Manczak, M. Neuroprotection of mitochondrial-targeted antioxidants in Alzheimer' disease. Paper presented at: Annual Meeting of the Society for Neuroscience; November 15-19, 2008; Washington, DC.Google Scholar
38.Szeto, HH. Development of mitochondria-targeted aromatic-cationic peptides for neurode-generative diseases. Ann N Y Acad Sci. 2008:1147:112–121.Google Scholar
39.Murphy, MRSmith, RA. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol. 2007:47:629–656.CrossRefGoogle ScholarPubMed
40.Doody, RS, Gavrilova, SI, Sano, M, et, al, and the dimebon investigators. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mildto-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 372(9634):207–215.CrossRefGoogle Scholar
41.Wu, J, Li, Q, Bezprozvanny, I.Evaluation of Dimebon in cellular model of Huntington's disease. Mol Neurodegener. 2008:3:15.Google Scholar