Growing evidence suggests that mitochondrial dysfunction is one of the key intracellular lesions associated with the pathogenesis of Alzheimer's disease (AD). Mitochondria, the powerhouses of the cell, participate in a number of physiological functions that include calcium homeostasis, signal transduction, and apoptosis. However, the pathophysiological mechanisms underlying the decline of mitochondrial vital functions leading to the dysfunction of mitochondria during AD are not well understood. Recent literature has observed the accumulation of Alzheimer's amyloid precursor protein (APP) and its C-terminal—cleaved product β-amyloid (Aβ) in the mitochondrial compartment. Furthermore, evidence also implicates that the accumulation of full-length APP and Aβ in the mitochondrial compartment has a causative role in impairing mitochondrial physiological functions. Here, we review the mode of mitochondrial transport of full-length APP and Aβ and its pathological implications in bringing about mitochondrial dysfunction as seen in AD. NEUROSCIENTIST 13(6):626—638, 2007. DOI: 10.1177/1073858407303536
Abramov AY, Canevari L., Duchen MR2004. βAmyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci24:565-75.
2.
Addya S., Anandatheerthavarada HK, Biswas G., Bhagwat SV, Mullick J., Avadhani NG1997. Targeting of NH2-terminal—processed microsomal protein to mitochondria: a novel pathway for the biogenesis of hepatic mitochondrial P450MT2. J Cell Biol139:589-99.
3.
Anandatheerthavarada HK, Biswas G., Mullick J., Sepuri NB, Otvos L., Pain D., and others.1999 . Dual targeting of cytochrome P4502B1 to endoplasmic reticulum and mitochondria involves novel signal activation by cyclic AMP-dependent phosphorylation at ser128. EMBO J18:5494-504.
4.
Anandatheerthavarada HK, Biswas G., Robin MA, Avadhani NG2003. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol161:41-54.
5.
Annaert WG, Levesque L., Craessaerts K., Dierinck I., Snellings G., Westaway D., and others.1999 . Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons. J Cell Biol147:277-94.
6.
Askanas V., McFerrin J., Baque S., Alvarez RB, Sarkozi E., Engel WK1996. Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle. Proc Natl Acad Sci USA93:1314-9.
7.
Bahmanyar S., Higgins GA, Goldgaber D., Lewis DA, Morrison JH, Wilson MC, and others.1987 . Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease. Science237:77-80.
8.
Baloyannis SJ2006. Mitochondrial alterations in Alzheimer's disease. J Alzheimer's Dis9:119-26.
9.
Basun H., Forssell LG, Wetterberg L., Winblad B.1991. Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer's disease. J Neural Transm Park Dis Dement Sect3:231-58.
Beal MF2005. Mitochondria take center stage in aging and neurodegeneration . Ann Neurol58:495-505.
12.
Borchelt DR, Thinakaran G., Eckman CB, Lee MK, Davenport F., Ratovitsky T., and others.1996 . Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron17:1005-13.
13.
Busciglio J., Pelsman A., Wong C., Pigino G., Yuan M., Mori H., and others.2002 . Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron33:677-88.
14.
Casley CS, Canevari L., Land JM, Clark JB, Sharpe MA2002. Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem80:89-100.
15.
Caspersen C., Wang N., Yao J., Sosunov A., Chen X., Lustbader JW, and others.2005 . Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J19:2040-1.
16.
Chang S., Ma T., Miranda D., Balestra ME, Mahley RW, Huang Y.2005. Lipid- and receptor-binding domains of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity . Proc Natl Acad Sci USA102:18694-9.
17.
Chen H., Chan DC2005. Emerging functions of mammalian mitochondrial fusion and fission. Human Mol Gen15(2):R283-9.
18.
Crouch PJ, Blake R., Duce JA, Ciccotosto GD, Li QX, Barnham KJ, and others.2005 . Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1—42. J Neurosci25:672-9.
19.
Cummings JL2000. Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurobiological basis. Neurobiol Aging21:845-61.
20.
David DC, Hauptmann S., Scherping I., Schuessel K., Keil U., Rizzu P., and others. 2005. Proteomic and functional analysis reveal a mitochondrial dysfunction in P301L Tau transgenic mice. J Biol Chem280:23802-14.
21.
Devi L., Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK2006. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci30:9057-68.
22.
Ellison DW, Beal MF, Mazurek MF, Bird ED, Martin JB1986. A postmortem study of amino acid neurotransmitters in Alzheimer's disease. Ann Neurol20:616-21.
23.
Endo T., Yamamoto H., Esaki M.2003. Functional cooperation and separation of translocators in protein import into mitochondria, the double-membrane bounded organelles . J Cell Sci116:3259-67.
24.
Falkevall A., Alikhani N., Bhushan S., Pavlov PF, Busch K., Johnson KA, and others. 2006. Degradation of the amyloid beta protein by the novel mitochondrial peptidasome, PreP. Biol Chem281:29096-104.
Gouras GK, Almeida CG, Takahashi RH2005. Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiol Aging26:1235-44.
27.
Grant SM, Shankar SL, Chalmers-Redman RM, Tatton WG, Szyf M., Cuello AC1999. Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). Neuroreport18:41-6.
28.
Hansson CA, Frykman S., Farmery MR, Tjernberg LO, Nilsberth C., Pursglove SE, and others. 2004. Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem279:51654-60.
29.
Hashimoto Y., Niikura T., Ito Y., Nishimoto I.2000. Multiple mechanisms underlie neurotoxicity by different types of Alzheimer's disease mutations of amyloid precursor protein. J Biol Chem275:34541-51.
Jeong SJ, Kim K., Suh YH1997. Age-related changes in the expression of Alzheimer's beta APP in the brain of senescence accelerated mouse (SAM)-P/10. Neuroreport8:1733-7.
32.
Keil U., Bonert A., Marques CA, Scherping I., Weyermann J., Strosznajder JB, and others. 2004. Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem279:50310-20.
33.
Leissring MA, Farris W., Wu X., Christodoulou DC, Haigis MC, Guarente L., and others.2004 . Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J383:439-46.
34.
Lin MT, Beal MF2006. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature443:787-95.
35.
Loeffler DA, LeWitt PA, Juneau PL, Sima AA, Nguyen HU, DeMaggio AJ, and others.1996 . Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res738:265-74.
36.
Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR1998. Copper, iron and zinc in Alzheimer's disease senile plaques . J Neurol Sci158:47-52.
37.
Lustbader JW, Cirilli M., Lin C., Xu HW, Takuma K., Wang N., and others.2004 . ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science304:448-52.
38.
Manczak M., Anekonda TS, Henson E., Park BS, Quinn J., Reddy PH2006. 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 Genet15:1437-49.
39.
Manfredi G., Beal MF2000. The role of mitochondria in the pathogenesis of neurodegenerative diseases. Brain Pathol10:462-72.
40.
Mattson MP1997. Central role of oxyradicals in the mechanism of Amyloid β-peptide toxicity. Alzheimer's Disease Review2:1-14.
41.
Maurer I., Zierz S., Moller HJ2000. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging21:455-62.
42.
McDermott JR, Smith AI, Iqbal K., Wisniewski HM1979. Brain aluminum in aging and Alzheimer disease. Neurology29:809-14.
43.
Mohs RC1996. The Alzheimer's disease assessment scale. Int Psychogeriatr8:195-203.
44.
Nazarali AJ, Reynolds GP1992. Monoamine neurotransmitters and their metabolites in brain regions in Alzheimer's disease: a postmortem study. Cell Mol Neurobiol12:581-7.
45.
Nicholls DJ, Budd SL2000. Mitochondria and neuronal survival. Physiol Rev80(1):315-60.
46.
Nunan J., Small DH2000. Regulation of APP cleavage by alpha-, beta-and gamma-secretases . FEBS Letters24184:1-5
47.
Offen D., Elkon H., Melamed E.2000. Apoptosis as a general cell death pathway in neurodegenerative diseases. J Neural Transm58:153-66.
48.
Park HJ, Kim SS, Seong YM, Kim KH, Goo HG, Yoon EJ, and others. 2006. Amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. J Biol Chem281: 34277-87.
49.
Parker WD Jr.1991. Cytochrome oxidase deficiency in Alzheimer's disease. Ann NY Acad Sci640:59-64.
50.
Prabu SK, Anandatheerthavarada HK, Raza H., Srinivasan S., Spear JF, Avadhani NG2006. Protein kinase A-mediated phosphorylation modulates cytochrome c oxidase function and augments hypoxia and myocardial ischemia-related injury . J Biol Chem281:2061-70.
51.
Price DL, Sisodia SS1998. Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci21:479-505.
52.
Reddy PH2006. Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease . J Neurochem96:1-13.
53.
Reddy PH, Beal MF2005. Are mitochondria critical in the pathogenesis of Alzheimer's disease?Brain Res Brain Res Rev49: 618-32.
54.
Rehling P., Wiedemann N., Pfanner N., Truscott KN2001. The mitochondrial import machinery for preproteins. Crit Rev Biochem Mol Biol36:291-336.
55.
Reinikainen KJ, Soininen H., Riekkinen PJ1990. Neurotransmitter changes in Alzheimer's disease: implications to diagnostics and therapy. J Neurosci Res27:576-86.
56.
Robin MA, Anandatheerthavarada HK, Biswas G., Naresh Babu VS, Gordon DM, Pain D., and others. 2002. Bimodal targeting of microsomal CYP2E1to mitochondria through activation of an N-terminal chimeric signal by cAMP mediated phosphorylation. J Biol Chem277:40583-93.
57.
Roesch K., Curran SP, Tranebjaerg L., Koehler CM2002. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum Mol Genet11: 477-86.
58.
Ronnett GV, Hester LD, Nye JF, Conners K., Snyder SH1990. Human cortical neuronal cell line: establishment from a patient with unilateral megalencephaly. Science248:603-5.
59.
Selkoe DJ1999. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature399:23-31.
60.
Shepherd CE, Bowes S., Parkinson D., Cambray-Deakin M., Pearson RC2000. Expression of amyloid precursor protein in human astrocytes in vitro: isoform-specific increases following heat shock. Neuroscience99:317-25.
61.
Sims NR1996. Energy metabolism, oxidative stress and neuronal degeneration in Alzheimer's disease. Neurodegeneration5:435-40.
62.
Stephenson DT, Rash K., Clemens JA1992. Amyloid precursor protein accumulates in regions of neurodegeneration following focal cerebral ischemia in the rat. Brain Res593:128-35.
63.
Sue W., Griffin T.2006. Inflammation and neurodegenerative diseases. Am J Clin Nutr83(suppl):470S—4S.
64.
Tabira T., Chui DH, Kuroda S.2002. Significance of intracellular Abeta42 accumulation in Alzheimer's disease. Front Biosci7:44-9.
65.
Taylor SW, Fahy E., Zhang B., Glenn GM, Warnock DE, Wiley S., and others.2003 . Characterization of the human heart mitochondrial proteome . Nat Biotechnol21:281-6.
66.
Thinakaran GJ1999. The role of presenilins in Alzheimer's disease. Clin Invest104:1321-7.
67.
Truscott KN, Pfanner N., Voos W.2001. Transport of proteins into mitochondria. Rev Physiol Biochem Pharmacol143:81-136.
68.
Xu J., Chen S., Ahmed H., Chen H., Ku G., Goldberg MP, and others.2001 . Amyloid-β peptides are cytotoxic to oligodendrocytes. J Neurosci21:RC118:1-5.
69.
Yamaguchi H., Yamazaki T., Ishiguro K., Shoji M., Nakazato Y., Hirai S.1992. Ultrastructural localization of Alzheimer amyloid beta/A4 protein precursor in the cytoplasm of neurons and senile plaque-associated astrocytes. Acta Neuropathol85:15-22.
70.
Zubenko GS2000. Neurobiology of major depression in Alzheimer's disease . Int Psychogeriatr12:217-30.
