Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease. 1. Introduction Each year, over 10 million people globally suffer from neurodegenerative diseases. This figure is expected to grow by 20% over the next decade as the aging population increases and lives longer. This disease group is the fourth biggest killer in the developed world after heart diseases, cancer, and stroke [1]. The most common neurodegenerative diseases are AD, Parkinson disease, Lewy body dementia, frontotemporal dementia, and amyotrophic lateral sclerosis [2]. The most widely recognized is AD, which is among the principal debilitating conditions of the current century. Approximately 24 million people worldwide suffer from dementia, 60% of cases being due to AD, which occurs in 1% of individuals aged 50 to 70 years old and dramatically increases to 50% of those over 70 years old [3]. Dramatically, these numbers are estimated to increase to 15 million in the next 40 years [4]. From the neuropathological point of view, AD is characterized by selective neuronal loss, marked synaptic alteration, morphological mitochondrial abnormalities, and Tau pathology. The
References
[1]
OECD, “Dementia prevalence,” in OECD, Health at a Glance: Europe 2010, pp. 54–55, OECD, 2010.
[2]
L. Bertram and R. E. Tanzi, “The genetic epidemiology of neurodegenerative disease,” The Journal of Clinical Investigation, vol. 115, no. 6, pp. 1449–1457, 2005.
[3]
C. P. Ferri, M. Prince, C. Brayne et al., “Global prevalence of dementia: a Delphi consensus study,” The Lancet, vol. 366, no. 9503, pp. 2112–2117, 2005.
[4]
American Health Assistance Foundation. Alzheimer disease research: about Alzheimer, http://www.ahaf.org/alzheimers/.
[5]
O. V. Forlenza, B. S. Diniz, and W. F. Gattaz, “Diagnosis and biomarkers of predementia in Alzheimer's disease,” BMC Medicine, vol. 8, article 89, 2010.
[6]
J. Gotz, A. Eckert, M. Matamales, et al., “Modes of Ab toxicity in Alzheimer’s disease,” Cellular and Molecular Life Science, vol. 68, no. 20, pp. 3359–3375, 2011.
[7]
A. Eckert, S. Hauptmann, I. Scherping et al., “Oligomeric and fibrillar species of β-amyloid (Aβ42) both impair mitochondrial function in P301L tau transgenic mice,” Journal of Molecular Medicine, vol. 86, no. 11, pp. 1255–1267, 2008.
[8]
S. Hauptmann, I. Scherping, S. Dr？se et al., “Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice,” Neurobiology of Aging, vol. 30, no. 10, pp. 1574–1586, 2009.
[9]
J. W. Lustbader, M. Cirilli, C. Lin et al., “ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease,” Science, vol. 304, no. 5669, pp. 448–452, 2004.
[10]
T. A. Clark, H. P. Lee, R. K. Rolston et al., “Oxidative stress and its implications for future treatments and management of alzheimer disease,” International Journal of Biomedical Science, vol. 6, no. 3, pp. 225–227, 2010.
[11]
X. Wang, B. Su, S. L. Siedlak et al., “Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 49, pp. 19318–19323, 2008.
[12]
N. Bogdanovic, M. Zilmer, K. Zilmer, A. Rehema, and E. Karelson, “The Swedish APP670/671 Alzheimer's disease mutation: the first evidence for strikingly increased oxidative injury in the temporal inferior cortex,” Dementia and Geriatric Cognitive Disorders, vol. 12, no. 6, pp. 364–370, 2001.
[13]
D. Praticò, K. Uryu, S. Leight, J. Q. Trojanoswki, and V. M. Y. Lee, “Increased lipid peroxidation precedes amyloid plaque formation in an animal model of alzheimer amyloidosis,” Journal of Neuroscience, vol. 21, no. 12, pp. 4183–4187, 2001.
[14]
A. Martínez-García, I. Sastre, M. Recuero et al., “PLA2G3, a gene involved in oxidative stress induced death, is associated with Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1181–1187, 2010.
[15]
T. Vargas, C. Ugalde, C. Spuch et al., “Aβ accumulation in choroid plexus is associated with mitochondrial-induced apoptosis,” Neurobiology of Aging, vol. 31, no. 9, pp. 1569–1581, 2010.
[16]
E. Perez-Gracia, R. Blanco, M. Carmona, E. Carro, and I. Ferrer, “Oxidative stress damage and oxidative stress responses in the choroid plexus in Alzheimer's disease,” Acta Neuropathologica, vol. 118, no. 4, pp. 497–504, 2009.
[17]
T. G. Freya and C. A. Mannellab, “The internal structure of mitochondria,” Trends in Biochemical Sciences, vol. 25, no. 7, pp. 319–324, 2000.
[18]
S. Anderson, A. T. Bankier, and B. G. Barrell, “Sequence and organization of the human mitochondrial genome,” Nature, vol. 290, no. 5806, pp. 457–465, 1981.
[19]
R. E. Giles, H. Blanc, H. M. Cann, and D. C. Wallace, “Maternal inheritance of human mitochondrial DNA,” Proceedings of the National Academy of Sciences of the United States of America, vol. 77, no. 11, pp. 6715–6719, 1980.
[20]
X. J. Chen and R. A. Butow, “The organization and inheritance of the mitochondrial genome,” Nature Reviews Genetics, vol. 6, no. 11, pp. 815–825, 2005.
[21]
J. A. Cam, C. V. Zerbinatti, J. M. Knisely, S. Hecimovic, Y. Li, and G. Bu, “The low density lipoprotein receptor-related protein 1B retains β-amyloid precursor protein at the cell surface and reduces amyloid-β peptide production,” The Journal of Biological Chemistry, vol. 279, no. 28, pp. 29639–29646, 2004.
[22]
Q. Liu, C. V. Zerbinatti, J. Zhang et al., “Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1,” Neuron, vol. 56, no. 1, pp. 66–78, 2007.
[23]
E. Waldron, C. Heilig, A. Schweitzer et al., “LRP1 modulates APP trafficking along early compartments of the secretory pathway,” Neurobiology of Disease, vol. 31, no. 2, pp. 188–197, 2008.
[24]
X. Alvira-Botero, R. Perez-Gonzalez, C. Spuch, et al., “Megalin interact with APP and the intracellular adaptor protein FE65 in neurons,” Molecular and Cellular Neuroscience, vol. 45, pp. 306–315, 2010.
[25]
R. Deane, S. D. Yan, R. K. Submamaryan et al., “RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain,” Nature Medicine, vol. 9, no. 7, pp. 907–913, 2003.
[26]
P. H. Reddy, “Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease,” Journal of Neurochemistry, vol. 96, no. 1, pp. 1–13, 2006.
[27]
L. Devi, B. M. Prabhu, D. F. Galati, N. G. Avadhani, and H. K. Anandatheerthavarada, “Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction,” Journal of Neuroscience, vol. 26, no. 35, pp. 9057–9068, 2006.
[28]
M. Manczak, T. S. Anekonda, E. Henson, B. S. Park, J. Quinn, and P. H. Reddy, “Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression,” Human Molecular Genetics, vol. 15, no. 9, pp. 1437–1449, 2006.
[29]
M. F. Beal, “Mitochondria take center stage in aging and neurodegeneration,” Annals of Neurology, vol. 58, no. 4, pp. 495–505, 2005.
[30]
P. H. Reddy, “Mitochondrial dysfunction in aging and Alzheimer's disease: strategies to protect neurons,” Antioxidants and Redox Signaling, vol. 9, no. 10, pp. 1647–1658, 2007.
[31]
K. Nuramaki, N. Murata, Y. Noda, et al., “SOD1 deficiency drives amyloid beta oligomerization and memory loss in a mouse model of Alzheimer’s diserase,” The The Journal of Biological Chemistry. In press.
[32]
M. Mancuso, D. Orsucci, A. LoGerfo, V. Calsolaro, and G. Siciliano, “Clinical features and pathogenesis of Alzheimer's disease: involvement of mitochondria and mitochondrial DNA,” Advances in Experimental Medicine and Biology, vol. 685, pp. 34–44, 2010.
[33]
D. F. F. Silva, A. R. Esteves, D. M. Arduino, C. R. Oliveira, and S. M. Cardoso, “Amyloid-β-induced mitochondrial dysfunction impairs the autophagic lysosomal pathway in a tubulin dependent pathway,” Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 565–581, 2011.
[34]
A. Eckert, K. Schmitt, and J. Gotz, “Mitochondrial dysfunction, the beginning of the end in Alzheimer’s disease? Separate and synergistic modes of tau and amyloid beta toxicity,” Alzheimer's Research & Therapy, vol. 3, article 15, 2011.
[35]
M. Manczak, B. S. Park, Y. Jung, and P. H. Reddy, “Differential expression of oxide phosphorylation genes in patients with Alzheimer’s disease: implications for early mitochondrial dysfunction and oxidative damage,” NeuroMolecular Medicine, vol. 5, no. 2, pp. 147–162, 2004.
[36]
K. Hirai, G. Aliev, A. Nunomura et al., “Mitochondrial abnormalities in Alzheimer's disease,” Journal of Neuroscience, vol. 21, no. 9, pp. 3017–3023, 2001.
[37]
A. Y. Abramov, L. Canevari, and M. R. Duchen, “beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons,” Journal of Neuroscience, vol. 24, no. 2, pp. 565–575, 2004.
[38]
G. E. Gibson and Q. Shi, “A mitocentric view of Alzheimer's disease suggests multi-faceted treatments,” Journal of Alzheimer's Disease, vol. 20, no. 2, pp. S591–S607, 2010.
[39]
M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature, vol. 443, no. 7113, pp. 787–795, 2006.
[40]
H. K. Anandatheerthavarada, G. Biswas, M. A. Robin, and N. G. Avadhani, “Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells,” Journal of Cell Biology, vol. 161, no. 1, pp. 41–54, 2003.
[41]
C. Caspersen, N. Wang, J. Yao et al., “Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease,” The FASEB Journal, vol. 19, no. 14, pp. 2040–2041, 2005.
[42]
P. Fernández-Vizarra, A. P. Fernández, S. Castro-Blanco et al., “Intra- and extracellular Aβ and PHF in clinically evaluated cases of Alzheimer's disease,” Histology and Histopathology, vol. 19, no. 3, pp. 823–844, 2004.
[43]
W. D. Parker, C. M. Filley, and J. K. Parks, “Cytochrome oxidase deficiency in Alzheimer's disease,” Neurology, vol. 40, no. 8, pp. 1302–1303, 1990.
[44]
W. D. Parker and J. K. Parks, “Cytochrome c oxidase in Alzheimer's disease brain: purification and characterization,” Neurology, vol. 45, no. 3, pp. 482–486, 1995.
[45]
S. M. Cardoso, I. Santana, R. H. Swerdlow, and C. R. Oliveira, “Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity,” Journal of Neurochemistry, vol. 89, no. 6, pp. 1417–1426, 2004.
[46]
V. Rhein, X. Song, A. Wiesner et al., “Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 47, pp. 20057–20062, 2009.
[47]
R. J. Mark, Z. Pang, J. W. Geddes, K. Uchida, and M. P. Mattson, “Amyloid β-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation,” Journal of Neuroscience, vol. 17, no. 3, pp. 1046–1054, 1997.
[48]
M. P. Mattson, “Pathways towards and away from Alzheimer's disease,” Nature, vol. 430, no. 7000, pp. 631–639, 2004.
[49]
H. Du, L. Guo, W. Zhang, M. Rydzewska, and S. Yan, “Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model,” Neurobiology of Aging, vol. 32, pp. 398–406, 2009.
[50]
U. Keil, S. Hauptmann, A. Bonert, I. Scherping, A. Eckert, and W. E. Müller, “Mitochondrial dysfunction induced by disease relevant AβPP and tau protein mutations,” Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 139–146, 2006.
[51]
P. I. Moreira, C. Carvalho, X. Zhu, M. A. Smith, and G. Perry, “Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology,” Biochimica et Biophysica Acta, vol. 1802, no. 1, pp. 2–10, 2010.
[52]
C. G. Glabe and R. Kayed, “Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis,” Neurology, vol. 66, no. 2, pp. S74–S78, 2006.
[53]
S. Chang, T. R. Ma, R. D. Miranda, M. E. Balestra, R. W. Mahley, and Y. Huang, “Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 51, pp. 18694–18699, 2005.
[54]
E. A. Schon and E. Area-Gomez, “Is Alzheimer's disease a disorder of mitochondria-associated membranes?” Journal of Alzheimer's Disease, vol. 20, no. 2, pp. S281–S292, 2010.
[55]
G. C. Kujoth and T. A. Prolla, “Evolving insight into the role of mitochondrial DNA mutations in aging,” Experimental Gerontology, vol. 43, no. 1, pp. 20–23, 2008.
[56]
G. C. Kujoth, P. C. Bradshaw, S. Haroon, and T. A. Prolla, “The role of mitochondrial DNA mutations in mammalian aging,” PLoS Genetics, vol. 3, no. 2, article e24, 2007.
[57]
S. A. Dogan and A. Trifunovic, “Modelling mitochondrial dysfunction in mice,” Physiological Research, vol. 60, pp. 61–70, 2011.
[58]
I. Bratic and A. Trifunovic, “Mitochondrial energy metabolism and ageing,” Biochimica et Biophysica Acta, vol. 1797, no. 6-7, pp. 961–967, 2010.
[59]
S. Z. Imam, B. Karahalil, B. A. Hogue, N. C. Souza-Pinto, and V. A. Bohr, “Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner,” Neurobiology of Aging, vol. 27, no. 8, pp. 1129–1136, 2006.
[60]
J. Sastre, A. Millan, J. G. De La Asuncion et al., “A ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress,” Free Radical Biology and Medicine, vol. 24, no. 2, pp. 298–304, 1998.
[61]
M. T. Lin, D. K. Simon, C. H. Ahn, L. M. Kim, and M. Flint Beal, “High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain,” Human Molecular Genetics, vol. 11, no. 2, pp. 133–145, 2002.
[62]
P. E. Coskun, M. F. Beal, and D. C. Wallace, “Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 29, pp. 10726–10731, 2004.
[63]
P. E. Coskun, J. Wyrembak, O. Derbereva et al., “Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia,” Journal of Alzheimer's Disease, vol. 20, no. 2, pp. S293–S310, 2010.
[64]
J. M. Shoffner, M. D. Brown, A. Torroni et al., “Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients,” Genomics, vol. 17, no. 1, pp. 171–184, 1993.
[65]
R. H. Swerdlow, “Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies,” Journal of Neuroscience Research, vol. 85, no. 15, pp. 3416–3428, 2007.
[66]
M. Newman, I. F. Musgrave, and M. Lardelli, “Alzheimer’s disease: amyloidogenesis, the presenilins and animal models,” Biochimica et Biophysica Acta, vol. 1772, no. 9, pp. 285–297, 2007.
[67]
E. Richartz, S. Noda, K. Schott, A. Günthner, P. Lewczuk, and M. Bartels, “Increased serum levels of CD95 in Alzheimer's disease,” Dementia and Geriatric Cognitive Disorders, vol. 13, no. 3, pp. 178–182, 2002.
[68]
K. Zarkovic, “4-Hydroxynonenal and neurodegenerative diseases,” Molecular Aspects of Medicine, vol. 24, no. 4-5, pp. 293–303, 2003.
[69]
E. A. Schon and S. Przedborski, “Mitochondria: the next neurodegeneration,” Neuron, vol. 70, pp. 1033–1053, 2011.
[70]
K. Brickley and F. A. Stephenson, “Trafficking kinesin protein (TRAK)-mediated transport of mitochondria in axons of hippocampal neurons,” The Journal of Biological Chemistry, vol. 286, no. 20, pp. 18079–18092, 2011.
[71]
F. Gillardon, W. Rist, L. Kussmaul et al., “Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition,” Proteomics, vol. 7, no. 4, pp. 605–616, 2007.
[72]
H. Du and S. S. Yan, “Mitochondrial medicine for neurodegenerative diseases,” International Journal of Biochemistry and Cell Biology, vol. 42, no. 5, pp. 560–572, 2010.
[73]
A. Eckert, S. Hauptmann, I. Scherping et al., “Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice,” Neurodegenerative Diseases, vol. 5, no. 3-4, pp. 157–159, 2008.
[74]
J. Yao, R. W. Irwin, L. Zhao, J. Nilsen, R. T. Hamilton, and R. D. Brinton, “Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 34, pp. 14670–14675, 2009.
[75]
H. Du, L. Guo, F. Fang et al., “Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease,” Nature Medicine, vol. 14, no. 10, pp. 1097–1105, 2008.
[76]
X. Wang, B. Su, H. G. Lee et al., “Impaired balance of mitochondrial fission and fusion in Alzheimer's disease,” Journal of Neuroscience, vol. 29, no. 28, pp. 9090–9103, 2009.
[77]
M. O. Dietrich, C. Spuch, D. Antequera et al., “Megalin mediates the transport of leptin across the blood-CSF barrier,” Neurobiology of Aging, vol. 29, no. 6, pp. 902–912, 2008.
[78]
R. Deane and B. V. Zlokovic, “Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease,” Current Alzheimer Research, vol. 4, no. 2, pp. 191–197, 2007.
[79]
C. Spuch and C. Navarro, “Expression and functions of LRP-2 in central nervous system: progress in understanding its regulation and the potential use for treatment of neurodegenerative diseases,” Recent Pat Immunology, Endocrine and metabolic Agents in Medicinal Chemistry, vol. 10, pp. 249–254, 2010.
[80]
C. Spuch and C. Navarro, “Expression and functions of LRP-2 in central nervous system: progress in understanding its regulation and the potential use for treatment of neurodegenerative diseases,” Endocrine, Metabolic & Immune Drug Discovery, vol. 4, pp. 190–205, 2010.
[81]
S. G. Anthony, H. M. Schipper, R. Tavares et al., “Stress protein expression in the Alzheimer-diseased choroid plexus,” Endocrine, Metabolic & Immune Drug Discovery, vol. 5, pp. 171–177, 2003.
[82]
E. Perez-Gracia, R. Blanco, M. Carmona, E. Carro, and I. Ferrer, “Oxidative stress damage and oxidative stress responses in the choroid plexus in Alzheimer's disease,” Acta Neuropathologica, vol. 118, no. 4, pp. 497–504, 2009.
[83]
T. Vargas, C. Ugalde, C. Spuch et al., “Aβ accumulation in choroid plexus is associated with mitochondrial-induced apoptosis,” Neurobiology of Aging, vol. 31, no. 9, pp. 1569–1581, 2010.
[84]
T. Vargas, D. Antequera, C. Ugalde, and C. Spuch, “Gelsolin restores Aβ -Induced alterations in choroid plexus epithelium,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 805405, 7 pages, 2010.
[85]
D. Antequera, T. Vargas, C. Ugalde et al., “Cytoplasmic gelsolin increases mitochondrial activity and reduces Aβ burden in a mouse model of Alzheimer's disease,” Neurobiology of Disease, vol. 36, no. 1, pp. 42–50, 2009.
[86]
P. H. Reddy and M. F. Beal, “Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease,” Trends in Molecular Medicine, vol. 14, no. 2, pp. 45–53, 2008.
