Abstract
β-amyloid (Aβ) deposition, in the form of plaques and amyloid angiopathy, and hyper-phosphorylated tau deposition forming neurofibrillary tangles, dystrophic neurites around β-amyloid plaques and neuropil threads, are neuropathological hallmarks of Alzheimer’s disease (AD) that accumulate in the brain with disease progression. These changes are accompanied by progressive loss of synapses and nerve cell death. Progressive cognitive impairment and dementia are the main neurological deficits. In addition, there is cumulative evidence demonstrating other metabolic disturbances that impair cell function and hamper neuron viability. The main components of the mitochondria are altered: complex IV of the respiratory chain is reduced; complex V which metabolizes ADP to form ATP is oxidatively damaged and functionally altered; and voltage-dependent anion channel VDAC, a major component of the outer mitochondrial membrane that regulates ion fluxes, is damaged as a result of oxidative stress. Mitochondria are a major source of reactive oxygen species that promote oxidative damage to DNA, RNA, proteins and lipids. Protein targets of oxidative damage are, among others, several enzymatic components of the glycolysis, lipid metabolism and cycle of the citric acid that fuel oxidative phosphorylation, mitochondrial respiration and energy production. The lipid composition of lipid rafts, key membrane specializations that facilitate the transfer of substrates, and protein-protein and lipid-protein interactions, is altered as a result of the abnormally low levels of n-3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid) that increase viscosity and augment energy consumption. Abnormal lipid raft composition may also modify the activity of key enzymes that modulate the cleavage of the amyloid precursor protein to form toxic Aβ. This is further complicated by the disruption of the complex VDAC with estrogen receptor α at the caveolae which participates, under physiological conditions, in the protection against β-amyloid. Together, all these alterations converge in reduced energy production and increased energy demands in altered cells. Cell exhaustion is suggested as being a determining element to interpret impaired neuron function, reduced molecular turnover, and enhanced cell death.
Similar content being viewed by others
References
Aksenov M, Aksenova M, Butterfield DA, Markesbery DW (2000) J Neurochem 74:2520–2527
Anderson RG (1998) Annu Rev Biochem 67:199–225
Bahamonde MI, Valverde MA (2003) Pflugers Arch 446:309–313
Baker MA, Lane DJ, Ly JD, De Pinto V, Lawen A (2004) J Biol Chem 279:4811–4819
Barnham KJ, Masters CL, Bush AI (2004) Nat Rev Drug Discov 3:205–214
Bàthori G, Parolini I, Tombola F, Szabò I, Messina A, Oliva M, De Pinto V, Lisanti M, Sargiacomo M, Zoratti M (1999) J Biol Chem 274:29607–29612
Blass JP (2000) Ann N Y Acad Sci 924:170–183
Braak H, Braak E, Peter J, Morrison JH (1999) Cerebral cortex, vol 14, Neurodegenerative and age-related changes in structure and function of cerebral cortex. In: Peters A, Morrison JH (eds). Kluwer Academic/Plenum Publishers, New York, Boston, Dordrecht, London, Moscow, pp 475–512
Brown DA, London E (2000) J Biol Chem 275:17221–17224
Butterfield DA, Kanski J (2001) Mech Ageing Dev 122:945–962
Butterfield DA, Poon HF, St Clair D, Keller JN, Pierce WM, Klein JB, Markesbery WR (2006) Neurobiol Dis 22:223–232
Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA (2002) J Neurochem 80:91–100
Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA (2002a) Free Radic Biol Med 33:562–571
Castegna A, Aksenov M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA (2002b) J Neurochem 82:1524–1532
Castegna A, Thongboonkerd V, Klein JB, Lynn B, Markesbery WR, Butterfield DA (2003) J Neurochem 85:1394–1401
Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA (2002) J Neurosci Res 70:357–360
Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C, Nixon RA (1995) Neuron 14:671–680
Chiara F, Castellaro D, Marin O, Petronilli V, Brusilow WS, Juhaszova M, Sollott SJ, Forte M, Bernardi P, Rasola A (2008) PLoS One 3:e1852
Colombini M (2007) Methods Cell Biol 80:241–260
Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ (2003) Proc Natl Acad Sci USA 100:11735–11740
Cosgrove JP, Church DF, Pryor WA (1987) Lipids 22:299–304
Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li QX, Barnham KJ, Curtain CC, Cherny RA, Cappai R, Dyrks T, Masters CL, Trounce IA (2005) J Neurosci 25:672–679
Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthvarada HK (2006) J Neurosci 26:9057–9068
Duyckaerts C, Dickson DW (2003) Neurodegeneration: the molecular pathology of dementia and movement disorders. In: Dickson DW (ed). ISN Neuropath, Basel, pp 47–68
Ehehalt R, Keller P, Haass C, Thiele C, Simons K (2003) J Cell Biol 160:113–123
Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, Ceccatelli S (2005) Cell Death Differ 12:1134–1140
Fiala JC, Feinberg M, Peters A, Barbas H (2007) Brain Struct Funct 212:195–207
Gibson GE, Ratan RR, Beal MF (2008) Ann NY Acad Sci vol 1147. Boston
Gillardon F, Rist W, Kussmaul L, Vogel J, Berg M, Danzer K, Kraut N, Hengerer B (2007) Proteomics 7:605–616
Halestrap AP (2009) J Mol Cell Cardiol 46:821–831
Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, New York
Hattori C, Asai M, Onishi H, Sasagawa N, Hashimoto Y, Saido TC, Maruyama K, Mizutani S, Ishiura S (2006) J Neurosci Res 84:912–917
Hayashi H, Mizuno T, Michikawa M, Haass C, Yanagisawa K (2000) Biochim Biophys Acta 1483:81–90
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) J Neurosci 21:3017–3023
Ikezu T, Trapp BD, Song KS, Schlegel A, Lisanti MP, Okamoto T (1998) J Biol Chem 273:10485–10495
Juhaszova M, Wang S, Zorov DB, Nuss HB, Gleichmann M, Mattoson MP, Sollott SJ (2008) Ann N Y Acad Sci 1123:197–212
Kidd M (1964) Brain 87:307–320
Kim HS, Lee JH, Lee JP, Kim EM, Chang KA, Park CH, Jeong SJ, Wittendorp MC, Seo JH, Choi SH, Suh YH (2002) NeuroReport 13:1989–1993
Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN (1992) J Neurochem 59:776–779
Korolainen MA, Auriola S, Nyman TA, Alafuzoff I, Pirttilä T (2005) Proteomic analysis of glial fibrillary acidic protein in Alzheimer’s disease and aging brain. Neurobiol Dis 20:858–870
Korolainen MA, Goldsteins G, Nyman TA, Alafuzoff I, Koistinaho J, Pirttilä T (2006) Aging 27:42–53
Lee SJ, Liyanage U, Bickel PE, **a W, Lansbury PT Jr, Kosik KS (1998) Nat Med 4:730–734
Lemasters JJ, Holmuhamedov E (2006) Biochim Biophys Acta 1762:181–90
Lin MT, Beal MF (2006) Nature 443:787–795
Lowe J, Mirra S, Hyman B, Dickson DW (2008) Greenfield’s neuropathology. In: Love S, Louis DN, Ellison DW (eds). Hodder Arnold, London, pp 1031–1152
Luse SA, Smith KR Jr (1964) Am J Pathol 44:553–563
Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy H (2006) Hum Mol Genet 15:1437–1449
Mannella CA, Kinnally KW (2009) J Bioenerg Biomembr 40:149–155
Marín R, Ramirez CM, Gonzalez M, Gonzalez-Munoz E, Zorzano A, Camps M, Alonso R, Diaz M (2007) Mol Memb Biol 24:148–160
Marlow L, Cain M, Pappolla MA, Sambamurti K (2003) J Mol Neurosci 20:233–239
Martín V, Fabelo N, Santpere G, Puig B, Ferrer I, Díaz M (2009) J Alzh Dis (Epub ahead of print)
Martínez A, Portero-Otin M, Pamplona R, Ferrer I (2009) Brain Pathol, (Epub ahead of print)
Maurer I, Zierz S, Moller HJ (2000) Neurobiol Aging 21:455–462
Mello CF, Sultana R, Piroddi M, Cai J, Pierce WM, Klein JB, Butterfield DA (2007) Neuroscience 147:674–679
Michel V, Bakovic M (2007) Biol Cell 99:129–140
Moreira PI, Santos MS, Oliveira CR (2007a) Antioxid Redox Signal 9:1621–1630
Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA, Zhu X, Perry G (2007b) J Neuropathol Exp Neurol 66:525–532
Mutisya EM, Bowling AC, Beal MF (1994) J Neurochem 63:2179–2184
Newman SF, Sultana R, Perluigi M, Coccia R, Cai J, Pierce WM, Klein JB, Turner DM, Butterfield DA (2007) J Neurosci Res 85:1506–1514
Nixon RA, Cataldo AM, Mathews PM (2000) Neurochem Res 9–10:1161–1172
Pamplona R, Dalfó E, Ayala V, Bellmunt MJ, Prat J, Ferrer I, Portero-Otín M (2005) J Biol Chem 280:21522–21530
Pamplona R, Barja G (2007) Ageing Res Rev 6:189–210
Perez-Gracia E, Torrejon-Escribano B, Ferrer I (2008) Acta Neuropathol 116:261–268
Pike LJ (2003) J Lipid Res 44:655–667
Ramirez CM, Gonzalez M, Díaz M, Alonso R, Ferrer I, Santpere G, Puig B, Meyer G, Marin R (2009) Mol Cell Neurosci. Jul 10 (Epub ahead of print)
Reed T, Perluigi M, Sultana R, Pierce WM, Klein JB, Turner DM, Coccia R, Markesbery WR, Butterfield DA (2008a) Neurobiol Dis 30:107–120
Reed TT, Pierce WM Jr, Turner DM, Markesbery WR, Butterfield DA (2008b) J Cell Mol Med. Aug 21 (Epub ahead of print)
Riddell DR, Christie G, Hussain I, Dingwall C (2001) Curr Biol 11:1288–1293
Rostovtseva TK, Bezrukov SM (2009) J Bioenerg Biomembr 40:163–170
Shoshan-Barmatz V, Israelson A, Brdiczka D, Sep SS (2006) Curr Phar Des 12:2249–2270
Shoshan-Barmatz V, Keinan N, Zaid H (2008) J Bioenerg Biomembr 40:183–191
Simons K, Ikonen E (1997) Nature 387:569–572
Starkov AA (2008) Ann N Y Acad Sci 1147:37–52
Sultana R, Boyd-Kimball D, Poon HF, Cai J, Pierce WM, Klein JB, Merchant M, Markesbery WR, Butterfield DA (2006a) Neurobiol Aging 27:1564–1576
Sultana R, Poon HF, Cai J, Pierce WM, Merchant M, Klein JB, Markesbery WR, Butterfield DA (2006b) Neurobiol Dis 22:76–87
Sultana R, Perluigi M, Butterfield DA (2009) Acta Neuropathol 118:131–150
Tan W, Colombini M (2007) Biochem Biophys Acta 1768:2510–2515
Terni B, Boada J, Portero-Otín M, Pamplona R, Ferrer I (2009) Brain Pathol. Feb 27 (Epub ahead of print)
Terry RD, Gonatas NK, Weiss M (1964) Am J Pathol 44:269–297
Thal DR, Rüb U, Orantes M, Braak H (2002) Neurology 58:1791–1800
Thinnes FP (2007) Mol Genet Metab 91:116–118
Vargas T, Ugaldse C, Spuch C, Antequera D, Morán MJ, Martín MA, Ferrer I, Bermejo-Pareja F, Carro E (2008) Neurobiol Aging. Jul 14 (Epub ahead of print)
Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, Parent AT, Sisodia S, Thinakaran G (2005) J Biol Chem 280:25892–25900
Wang X, Su B, Perry G, Smith MA, Zhu X (2007) Free Radic Biol Med 43:1569–1573
Zhu X, Perry G, Moreira PI, Aliev G, Cash AD, Hirai K, Smith MA (2006) J Alzheimer’s Dis 9:147–153
Author information
Authors and Affiliations
Corresponding author
Additional information
Special minireview issue of the Journal of Bioenergetics and Biomembranes related to mitochondria and Alzheimer’s disease: Mitochondrial matters of the brain: amyloid formation and Alzheimer’s disease.
Rights and permissions
About this article
Cite this article
Ferrer, I. Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer’s disease. J Bioenerg Biomembr 41, 425–431 (2009). https://doi.org/10.1007/s10863-009-9243-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10863-009-9243-5