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Mechanisms of cell death in neurodegenerative disorders

  • Conference paper
Advances in Dementia Research

Abstract

Objective: Progressive cell loss in specific neuronal populations is the prominent pathological hallmark of neurodegenerative diseases, but its molecular basis remains unresolved. Apoptotic cell death has been implicated as a general mechanism in Alzheimer disease (AD) and other neurodegenerative disorders. However, DNA fragmention in neurons is too frequent to account for the continuous loss in these slowly progressive diseases.

Material and methods: In 9 cases of morphologically confirmed AD (CERAD criteria, Braak stages 5 or 6), 5 cases of Parkinson disease (PD) and 3 cases each of Dementia with Lewy bodies (DLB), Progressive Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA), and 7 age-matched controls, the TUNEL method was used to detect DNA fragmentation, and immunohistochemistry for an array of apoptosis-related proteins (ARP), protooncogenes, and activated caspase-3 were performed.

Results: In AD, a considerable number of hippocampal neurons showed DNA fragmentation with a 3 to 5.7 fold increase related to neurofibrillary tangles and amyloid deposits, but only exceptional neurons displayed apoptotic morphology (1 in 1100–5000) and cytoplasmic immunoreactivity for ARPs and activated caspase-3 (1 in 2600 to 5650 hippocampal neurons), whereas no neurons were labeled in age-matched controls. Caspase-3 immunoreactivity was seen in granules of granulovacular degeneration, only rarely colocalized with tau-immunoreactivity. In PD, DLB, and MSA, TUNEL positivity and expression of ARPs or activated caspase-3 was only seen in microglia, rare astrocytes and in oligodendroglia with cytoplasmic inclusions in MSA, but not in nigral or other neurons with or without Lewy bodies. In PSP, only single neurons but oligodendrocytes, some with tau deposits, in brainstem tegmentum and pontine nuclei were TUNEL-positive and expressed both ARPs and activated caspase-3.

Conclusions: These data provide evidence for extremely rare apoptotic neuronal death in AD compatible with the progression of neuronal degeneration in this chronic disease. In other neurodegenerative disorders, apoptosis mainly involves microglia and oligodendroglia, while alternative mechanisms of neuronal death may occur. Susceptible cell populations in a proapoptotic environment show increased vulnerability towards metabolic and other pathogenic factors, with autophagy as a possible protective mechanism in early stages of programmed cell death. The intracellular cascade leading to cell death still awaits elucidation.

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References

  • Adamec E, Vonsattel JP, Nixon RA (1999) DNA strand breaks in Alzheimer’s disease. Brain Res 849: 67 – 77

    Article  PubMed  CAS  Google Scholar 

  • Anderson AJ, Su JH, Cotman CW (1996) DNA damage and apoptosis in Alzheimer’s disease: colocalization with c-Jun immunoreactivity, relationship to brain area and effect of post mortem delay. J Neurosci 16: 1710 – 1719

    PubMed  CAS  Google Scholar 

  • Anglade P, Vyas S, Javoy-Agid F, Herrero M-T, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12: 25 – 31

    PubMed  CAS  Google Scholar 

  • Arendt T, Holzer M, Fruth R, Brückner MK, Gärtner U (1998) Phosphorylation of tau, Aβ-formation, and apoptosis after in vivo inhibition of PP-1 and PP-2A. Neurobiol Aging 19: 3 – 13

    Article  PubMed  CAS  Google Scholar 

  • Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8: 711 – 715

    Article  PubMed  CAS  Google Scholar 

  • Banati RB, Daniel SE, Path MRC, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 13: 221 – 227

    Article  PubMed  CAS  Google Scholar 

  • Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche O, Seitelberger F, Grundke-Iqbal I, Wisniewski HM (1989) Accumulation of abnormally phosphory- lated t precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477: 90 – 99

    Article  PubMed  CAS  Google Scholar 

  • Bergeron C, Davis A, Lang AE (1998) Corticobasal ganglionic degeneration and progressive supranuclear palsy presenting with cognitive decline. Brain Pathol 8: 355 – 365

    Article  PubMed  CAS  Google Scholar 

  • Boonman Z, Isacson O (1999) Apoptosis in neuronal development and transplantation: role of caspases and trophic factors. Exp Neurol 156: 1 – 18

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239 – 259

    Article  PubMed  CAS  Google Scholar 

  • Braak E, Braak H, Mandelkow E-M (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neurophil threads. Acta Neuropathol 87: 554 – 567

    Article  PubMed  CAS  Google Scholar 

  • Bredesen DE (1995) Neural apoptosis. Ann Neurol 38: 839 – 851

    Article  PubMed  CAS  Google Scholar 

  • Burke RE, Kholodilov NG (1998) Programmed cell death: does it play a role in Parkinson’s disease? Ann Neurol 44 [Suppl 1]: S126 – S133

    PubMed  CAS  Google Scholar 

  • Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RLM, Dragunow M (1998) Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington’s-disease striatum. Neuroscience 87: 49 – 53

    Article  PubMed  CAS  Google Scholar 

  • Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RLM, Dragunow M (1998) Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington’s-disease striatum. Neuroscience 87: 49 – 53

    Article  PubMed  CAS  Google Scholar 

  • Charles PD, Robertson D, Kerr LD, Lonce S, Austin MT, Gelbman BD, Whetsell WO, Davis TL (1997) Evidence of apoptotic cell death in multiple-system atrophy. Ann Neurol 42: 408 – 409

    Google Scholar 

  • Clarke PGH (1990) Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol 181: 195 – 213

    Article  PubMed  CAS  Google Scholar 

  • Clarke PGH (1999) Apoptosis versus necrosis. In: Koliatsosue M, Ratan RR (eds), Cell death and disease of the nervous system, Humana Press, Totowa NY, pp 3 – 28

    Google Scholar 

  • Cotman CW (1998) Apoptosis decision cascades and neuronal degeneration in Alzheimer’s disease. Neurobiol Aging 19 [Suppl 1]: S29 – S32

    Article  PubMed  CAS  Google Scholar 

  • Cotman CW, Su JH (1996) Mechanisms of neuronal cell death in Alzheimer’s disease. Brain Pathol 6: 493 – 506

    Article  PubMed  CAS  Google Scholar 

  • Cotman CW, Ivins KH, Anderson AJ (1999) Apoptosis in Alzheimer disease. In: Terry RD, Katzman R, Black KJ, Sisodia SS (eds), Alzheimer disease, 2nd edn, Lippincott, Williamns & Wilkins, Philadelphia, pp. 347 – 357

    Google Scholar 

  • de la Monte SM, Sohn YK, Wands JR (1997) Correlates of p53- and Fas (CD95)- mediated apoptosis in Alzheimer’s disease. J Neurol Sci 152: 73 – 83

    Article  PubMed  Google Scholar 

  • de la Monte SM, Sohn YK, Ganju N, Wands JR (1998) p53- and CD95-associated apoptosis in neurodegenerative diseases. Lab Invest 78: 401–411

    Google Scholar 

  • Dragunow M, Faull R, Lawlor P, Beilharz EJ, Singleton K, Walker EB, Mee E (1995) In situ evidence for DNA fragmentation in Huntington’s disease striatum and Alzheimer’s disease temporal lobes. Neuroreport 6: 1053 – 1057

    Article  PubMed  CAS  Google Scholar 

  • Duan W, Zhang Z, Gash DM, Mattson MP (1999) Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson’s disease. Ann Neurol 46: 587 – 597

    Article  PubMed  CAS  Google Scholar 

  • Galvin JE, Lippa CF (1999) Apoptosis in familial Alzheimer’s disease (abstr.). Ann Neurol 46: 452

    Google Scholar 

  • Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW (1999) Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid- beta precursor protein and amyloidogenic A beta peptide formation. Cell 97: 395 – 406

    Article  PubMed  CAS  Google Scholar 

  • Giannakopoulos P, Kövari E, Savioz A, De Bilabao F, Dubois-Dauphin M, Hof PR, Bouras C (1999) Differential distribution of presenilin-1, Bax, and Bcl-X in Alzheimer’s disease and frontotemporal dementia. Acta Neuropathol 98: 141 – 149

    Article  PubMed  CAS  Google Scholar 

  • Gleckman AM, Jiang Z, Liu Y, Smith TW (1999) DNA fragmentation in neurons and glial cells indicates cellular injury but not apoptosis in Pick’s disease. Acta Neuropathol 98: 55 – 61

    Article  PubMed  CAS  Google Scholar 

  • Gold R, Schmied M, Giegerich G, Breitschopf H, Hartung HP, Toyka K, Lassmann H (1994) Differentiation between cellular apoptosis and necrosis by combined use of in situ tailing and nick translation techniques. Lab Invest 71: 219 – 225

    PubMed  CAS  Google Scholar 

  • Graeber MB, Grasbon-Frodl E, Abell-Aleff P, Kösel S (1999) Nigral neurons are likely to die of a mechanism other than classical apoptosis in Parkinson’s disease. Parkinsonism Relat Disord 5: 187 – 192

    Article  PubMed  CAS  Google Scholar 

  • Grohshal N, Smiley JF, DeMaggio AJ, Hoekstra MF et al (1999) A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer’s disease. Am J Pathol 155: 1163 – 1172

    Article  Google Scholar 

  • Gschwind M, Huber G (1995) Apoptotic cell death induced by (3-amyloid 1–42 peptide is cell type dependent. J Neurochem 65: 292 – 300

    Article  PubMed  CAS  Google Scholar 

  • Guo Q, Sopher BL, Furukawa K, Pham DG, Robinson N, Martin GM, Mattson MP (1997) Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide: involvement of calcium and oxyradicals. J Neurosci 17: 4212 – 4222

    PubMed  CAS  Google Scholar 

  • Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM, Mattson MP (1998) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nature Med 4: 957 – 962

    Article  PubMed  CAS  Google Scholar 

  • Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP (1999a) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin- 1 mutant knock-in mice. Nature Med 5: 101 – 106

    Article  CAS  Google Scholar 

  • Guo Q, Sebastian L, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP (1999b) Increased vunerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid β-peptide toxicity: central roles of superoxide production and caspase activation. J Neurochem 72: 1019 – 1029

    Article  CAS  Google Scholar 

  • Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S et al (2000) Caspase-3. A vulnerability factor and final effector in apopotitc death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci USA 97: 2875 – 2880

    Article  PubMed  CAS  Google Scholar 

  • Hauw J-J, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I (1994) Preliminary NINDS neuropathologic criteria for Steele- Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44: 2015 – 2019

    PubMed  CAS  Google Scholar 

  • Hockenbery D (1995) Defining apoptosis. Am J Pathol 146: 16 – 19

    PubMed  CAS  Google Scholar 

  • Ivins KJ, Thornton PL, Rohn TT, Cotman CW (1999) Neuronal apoptosis induced by β- amyloid is mediated by caspase-8. Neurobiol Dis 6: 440 – 449

    Article  PubMed  CAS  Google Scholar 

  • Jellinger KA (1999a) Mechanisms of cell death in Parkinson’s disease and related disorders. Neurosci News 2: 27 – 35

    CAS  Google Scholar 

  • Jellinger KA (1999b) Is there apoptosis in Lewy body disease? Acta Neuropathol 97: 413 – 415

    Article  CAS  Google Scholar 

  • Jellinger KA (2000) Cell death mechanisms in Parkinson’s disease. J Neural Transm 107: 1 – 29

    Article  PubMed  CAS  Google Scholar 

  • Jeon BS, Kholodilov NG, Oo TF, Kim SY, Tomaselli KJ, Srinivasan A, Stefanis L, Burke RE (1999) Activation of caspase-3 in developmental models of programmed cell death in neurons of the substantia nigra. J Neurochem 73: 322 – 333

    Article  PubMed  CAS  Google Scholar 

  • Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C (1999) Inhibition of NF- KBpotentiates amyloid β-mediated neuronal apoptosis. Proc Natl Acad Sci USA 96: 9409 – 9414

    Article  PubMed  CAS  Google Scholar 

  • Keller JN, Guo Q, Holtsberg FW, Bruce-Keller AJ, Mattson MP (1998) Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J Neurosci 18: 4439 – 4450

    PubMed  CAS  Google Scholar 

  • Kihira T, Yoshida S, Hironishi M, Wakayama I, Yase Y (1998) Neuronal degeneration in amyotrophic lateral sclerosis is TI mediated by a possible mechanism different from classical apoptosis. Neuropathology 18: 301 – 308

    Article  Google Scholar 

  • Kingsbury AE, Fester OJF, Nisbet AP, et al (1995) Tissue pH as an indicator of mRNA preservation in post-mortem brain. Mol Brain Res 28: 311-318 Kingsbury AE, Marsden CD, Foster OJF (1998) DNA fragmentation in human substantia nigra: apoptosis or perimortem effect? Mov Disord 13: 877 – 884

    Google Scholar 

  • Kitamura Y, Shimohama S, Kamoshima W, Ota T, Matsuoka Y, Nomura Y, Smith MA, Perry G, Whitehouse PJ, Taniguchi T (1998) Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer’s disease. Brain Res 780: 260 – 269

    Google Scholar 

  • Kösel S, Egensperger R, v. Eitzen U, Mehraein P, Graeber M (1997) On the question of apootosis in the Parkinsonian substantia nigra. Acta Neuropathol 93: 105 – 108

    Article  PubMed  Google Scholar 

  • Kwok JBJ, Li Q-X, Hallupp M, Whyte S et al (2000) Novel Leu723Pro amyloid precursor protein mutation increases amyloid (342(43) peptide levels and induces apoptosis. Ann Neurol 47: 249 – 253

    Article  PubMed  CAS  Google Scholar 

  • Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1- methyl-4-phenyl-l,2,3,6-tetrahydropyridine exposure. Ann Neurol 46: 598 – 605

    Article  PubMed  CAS  Google Scholar 

  • Lantos PL (1999) The definition of multiple system atrophy: A review of recent developments. J Neuropathol Exp Neurol 57: 1099 – 1111

    Article  Google Scholar 

  • Lassman H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, Jellinger K, Wisniewski HM (1995) Cell death in Alzheimer’s disease evaluated by DNA fragmentation in situ. Acta Neuropathol 89: 35 – 41

    Article  Google Scholar 

  • Li YP, Bushnell AF, Lee CM, Perlmutter LS, Wong SK (1996) β-amyloid induces apoptosis in human-derived neurotypic SH-SY5Y cells. Brain Res 738:196–204

    Google Scholar 

  • Lu DC, Rabizadeh S, Chandra S, Shayya RF, Ellerby LM, Ye X, Salvesen GS, Koo EH, Bredesen DF (2000) A second cytotoxic proteolytic peptide derived from amyloid β- protein precursor. Nat Med 6: 397 – 404

    Article  PubMed  CAS  Google Scholar 

  • Lucassen PJ, Chung WCJ, Kamphorst W, Swaab DF (1997) DNA damage distribution in the human brain as shown by in situ end labelling. Area-specific differences in aging and Alzheimer’s disease in the absence of apoptotic morphology. J Neuropathol Exp Neurol 887 – 900

    Google Scholar 

  • MacGibbon GA, Lawlor PA, Walton M, Sirimanne E, Faull RLM, Synek B, Mee E, Connor B, Dragunow M (1997) Expression of Fos, Jun, and Krox family proteins in Alzheimer’s disease. Exp Neurol 147: 316 – 332

    Article  PubMed  CAS  Google Scholar 

  • Marcus DL, Thomas CG, Levin R, Golomb J, Recht P, Freedman ML (1996) Evidence for apoptosis in Alzheimer’s disease. J Invest Med 44: 308A Marcus DL, Strafaci JA, Miller DC, Masia S, Thomas CG, Rosman J, Hussain S, Freedman ML (1998) Quantitative neuronal c-Fos and c-Jun expression in Alzheimer’s disease. Neurobiol Aging 19: 393 – 400

    Google Scholar 

  • Marshall KA, Daniel SE, Cairns N, Jenner P, Halliwell B (1997) Upregulation of the anti- apoptotic protein Bcl-2 may be early event in neurodegeneration: studies on Parkinson’s incidental Lewy body disease. Biochem Biophys Res Commun 240: 84 – 87

    Article  PubMed  CAS  Google Scholar 

  • Martin LJ (1999) Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 58: 459 – 471

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Mallory M, Alford M, Tanaka S, Hansen LA (1998) Caspase dependent DNA fragmentation might be associated with excitotoxicity in Alzheimer disease. J Neuropathol Exp Neurol 57: 1041 – 1052

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP, Partin J, Begley JG (1998) Amyloid β-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 807: 167 – 176

    Article  PubMed  CAS  Google Scholar 

  • McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Loverstone S, Collerton D, Jansen ENH, de Vos RAI, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB International Workshop. Neurology 47: 1113 – 1124

    PubMed  CAS  Google Scholar 

  • McShea A, Harris PLR, Webster KR, Wahl AF, Smith MA (1997) Abnormal expression of the cell cycle regulators P 16 and CDK4 in Alzheimer’s disease. Am J Pathol 50: 1933 – 1939

    Google Scholar 

  • Michel PP, Lambeng N, Ruberg M (1999) Neuropharmacologic aspects of apoptosis: Significance for neurodegenerative diseases. Clin Neuropharmacol 22: 137 – 150

    PubMed  CAS  Google Scholar 

  • Micheli A, Atzori C, Pival R, Tortarolo M, Girelli M, Schiffer D, Bendotti C (1999) Lack of apoptosis in mice with ALS. Nat Med 5: 966 – 967

    Article  CAS  Google Scholar 

  • Milligan CE (2000) Caspase cleavage of APP results in a cytotoxic proteolytic peptide. Nat Med 6: 385 – 386

    Article  PubMed  CAS  Google Scholar 

  • Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathological assessment of Alzheimer’s disease. Neurology 41: 479 – 486

    PubMed  CAS  Google Scholar 

  • Mochizuki H, Mori H, Mizuno Y (1997) Apoptosis in neurodegenerative disorders. J Neural Transm [Suppl 50]: 125 – 140

    Google Scholar 

  • Mogi M, Togari A, Kondo T, Mizono Y et al (2000) Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from Parkinsonian brains. J Neural Transm 107: 335 – 341

    Article  PubMed  CAS  Google Scholar 

  • Morsch R, Simon W, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Appl Neurol 58: 188 – 197

    Article  CAS  Google Scholar 

  • Morrison BM, Hof PR, Morrison JH (1998) Determinants of neuronal vulnerability in neurodegenerative diseases. Ann Neurol 44 [Suppl 1]: S32 – S44

    PubMed  CAS  Google Scholar 

  • Nagy ZS, Esiri MM (1997) Apoptosis-related protein expression in the hippocampus of Alzheimer’s disease. Neurobiol Aging 18: 655 – 671

    Article  Google Scholar 

  • Nagy Z, Esiri MM, Smith AD (1997) Expression of cell division markers in the hippocampus of Alzheimer’s disease and other neurodegenerative conditions. Acta Neuropathol 93: 294 – 300

    Article  PubMed  CAS  Google Scholar 

  • Nishimura T, Akiyama H, Yonehara S, Kondo H, Ikeda K, Kato M, Iseki E, Kosaka K (1995) Fas antigen expression in brains of patients with Alzheimer-type dementia. Brain Res 695: 137 – 145

    Article  PubMed  CAS  Google Scholar 

  • Ohyagi Y, Yamada T, Asahara H, Taniwaki T, Nakabeppu Y, Younkin S, Kira J (1999) Amyloid-β protein 42 forms a 24-kd complex in normal cells and is deposited in apoptotic neurons (abstr). Ann Neurol 46: 453 Ohyagi Y, Yamada T, Nishioka K, Clarke NJ et al (2000) Selective increase in cellular Aβ42 is related to apoptosis but not necrosis. Neuroreport 11: 167 – 171

    Article  Google Scholar 

  • Olanow CW, Jenner P, Tatton N, Tatton WG (1998) Neurodegeneration in Parkinson’s disease. In: Jankovic J, Tolosa E (eds) Parkinson’s disease and movement disorders, 3rd edn. Williams & Wilkins, Baltimore, pp 67 – 103

    Google Scholar 

  • Olanow CW, Jenner P, Tatton N, Tatton WG (1998) Neurodegeneration in Parkinson’s disease. In: Jankovic J, Tolosa E (eds) Parkinson’s disease and movement disorders, 3rd edn. Williams & Wilkins, Baltimore, pp 67 – 103

    Google Scholar 

  • Patel T, Gores GJ, Kaufmann SH (1996) The role of proteases during apoptosis. FASEB J 10: 587 - 597

    PubMed  CAS  Google Scholar 

  • Perry G, Numomura A, Smith MA (1998a) A suicide note from Alzheimer disease neurons? Nat Med 4: 897 – 898

    Article  CAS  Google Scholar 

  • Perry G, Numomura A, Lucassen PJ, Lassmann H, Smith MA (1998b) Apoptosis and Alzheimer’s disease. Science 282: 1265 Pettman B, Henderson CE (1998) Neuronal cell death. Neuron 20: 633 – 647

    Google Scholar 

  • Probst-Cousin S, Rickert CH, Schmid KW, Gullotta F (1998) Cell mechanisms in multiple system atrophy. J Neuropathol Exp Neurol 57: 814 – 821

    Article  PubMed  CAS  Google Scholar 

  • Robertson GS, Crocker SJ, Nicholson DW, Schulz JB (2000) Neuroprotection by the inhibition of apoptosis. Brain Pathol 10: 283 – 292

    Article  PubMed  CAS  Google Scholar 

  • Selznick LA, Holtzman DM, Han BH, Gokder M, Srinivasan AN, Johnson MJ, Roth KA (1999) In situ immunodetection of neuronal caspase-3 activation in Alzheimer disease. J Neuropathol Exp Neurol 58: 1020 – 1026

    Article  PubMed  CAS  Google Scholar 

  • Selznick LA, Zheng TS, Flavell RA, Rakic P, Roth KA (2000) Amyloid beta-induced neuronal death is Bax-dependent but Caspase-independent. J Neuropathol Exp Neurol 59: 271 – 279

    PubMed  CAS  Google Scholar 

  • Sheng JG, Mrak RE, Griffin WST (1998) Progressive neuronal DNA damage associated with neurofibrillary tangle formation in Alzheimer’s disease. J Neuropathol Exp Neurol 57: 323 – 328

    Article  PubMed  CAS  Google Scholar 

  • Smale JG, Nichols NR, Brady DR, Finch CE, HortonWE Jr (1995) Evidence for apoptotic cell death in Alzheimer’s disease. Exp Neurol 133: 225 – 230

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan A, Roth KA, Sayers RO, Shindler KS, Wong AM, Fritz LC, Tomaselli K (1998) In situ immunodetection of activated caspase-3 in apoptotic neurons in the developing nervous system. Cell Death Differ 5: 1004 – 1016

    Article  PubMed  CAS  Google Scholar 

  • Stadelmann C, Brück W, Bancher C, Jellinger K, Lassmann H (1998) Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability but not apoptosis. J Neuropathol Exp Neurol 57: 456 – 464

    Article  PubMed  CAS  Google Scholar 

  • Stadelmann C, Deckwerth TL, Scrinivasan A, Bancher C, Brück W, Jellinger K, Lassmann H (1999) Activation of caspase-3 in single apopototic neurons and granules of granulovacuolar degeneration in Alzheimer disease and Down’s syndrome: a role for autophagy as antiapoptotic counterregulatory mechanism ? Am J Pathol (submitted) Su JH, Satou T, Anderson AJ, Cotman CW (1996) Up-regulation of Bcl-2 is associated with neuronal DNA damage in Alzheimer’s disease. Neuroreport 7: 437 – 440

    Google Scholar 

  • Su JH, Deng GM, Cotman CW (1997) Bax protein expression is increased in Alzheimer’s brain: correlations with DNA damage, Bcl-2 expression, and brain pathology. J Neuropathol Exp Neurol 56: 86 – 93

    Article  PubMed  CAS  Google Scholar 

  • Tan Z, Sun N, Schreiber SS (1998) Immunohistochemical localization of redox factor-1 (Ref-1) in Alzheimer’s hippocampus. NeuroReport 9: 2749 – 2752

    CAS  Google Scholar 

  • Tatton WG, Chalmers-Redman RME, Rideout HJ, Tatton NA (1999) Mitochondrial permeability in neuronal death: possible relevance to the pathogenesis of Parkinson’s disease. Parkinsonism Relat Disord 5: 221 – 229

    Article  PubMed  CAS  Google Scholar 

  • Thomas LB, Gates DJ, Richfield EK, O’Brien TF, Schweitzer JB, Steindler DA (1995) DNA end labeling (TUNEL) in Huntington’s disease and other neuropathological conditions. Exp Neurol 133: 265 – 272

    Article  PubMed  CAS  Google Scholar 

  • Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281: 1312 – 1316

    Article  PubMed  CAS  Google Scholar 

  • Tompkins MM, Hill WD (1997) Contribution of somal Lewy bodies to neuronal death. Brain Res 775: 24 – 29

    Article  PubMed  CAS  Google Scholar 

  • Tompkins MM, Basgall EJ, Zamrini E, Hill WD (1997) Apoptotic-like changes in Lewy body-associated disorders and normal aging in substantia nigral neurons. Am J Pathol 150: 119 – 131

    PubMed  CAS  Google Scholar 

  • Torp R, Su JH, Deng G, Cotman CW (1998) GADD45 is induced in Alzheimer’s disease, and protects against apoptosis in vitro. Neurobiol Dis 5: 245 – 252

    Article  PubMed  CAS  Google Scholar 

  • Tortosa A, Blanco R, Ferrer I (1998a) Bcl-2 and Bax protein expression in neurofibrillary tangles in progressive supranuclear palsy. NeuroReport 9: 1049 – 1052

    CAS  Google Scholar 

  • Tortosa A, Lopez W, Ferrer I (1998b) Bcl-2 and Bax protein expression in Alzheimer’s disease. Acta Neuropathol 95: 407 – 412

    Article  CAS  Google Scholar 

  • Trojanowski JQ, Goedert M, Iwatsubo T, Lee VMY (1998) Fatal attractions — abnormal protein aggregation and neuron death in Parkinson’s disease and Lewy body- dementia. Cell Death Differ 5: 832 – 837

    Article  PubMed  CAS  Google Scholar 

  • Troncoso JC, Sukhov RR, Kawas CH, Koliatsos VE (1996) In situ labeling of dying cortical neurons in normal aging and in Alzheimer’s disease. Correlations with senile plaques and disease progression. J Neuropathol Exp Neurol 55: 1134 – 1142

    Article  PubMed  CAS  Google Scholar 

  • Troost D, Aten J, Morsink F, de Jong JMBV (1995) Apoptosis in amyotrophic lateral sclerosis is not restricted to motor neurons: Bcl-2 expression is increased in unaffected post-central gyrus. Neuropathol Appl Neurobiol 21: 498 – 504

    Article  PubMed  CAS  Google Scholar 

  • Tu P-H, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM-Y (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble a-synuclein. Ann Neurol 44: 415 – 422

    Article  PubMed  CAS  Google Scholar 

  • Vito P, Ghayur T, D’Adamio L (1997) Generation of antiapoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage. J Biol Chem 272: 28315 – 28320

    Article  PubMed  CAS  Google Scholar 

  • Vyas S, Javoy-Agid F, Herrero MT, Strada O, Boissiere F, Hibner U, Agid Y (1997) Expression of Bel 2 in adult human brain regions with special reference to neurodegenerative disorders. J Neurochem 69: 223 – 231

    Article  PubMed  CAS  Google Scholar 

  • Wang KKW (2000) Calpain and caspase; can you tell the difference? Trends Neurol Sci 23: 20 – 26

    Article  Google Scholar 

  • Wilson CA, Roms RW, Lee M-Y (1999) Intracellular APP processing and Aβ production in Alzheimer disease. J Neuropathol Exp Neurol 58: 787 – 794

    Article  PubMed  CAS  Google Scholar 

  • Wolozin B, Iwasaki K, Vito P, et al (1996) Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 274: 1710

    Article  PubMed  CAS  Google Scholar 

  • Wüllner U, Kornhuber J, Weller M, Schulz JB, Loschmann PA, Riederer P (1999) Cell death and apoptosis regulating proteins in Parkinson’s disease — a cautionary note. Acta Neuropathol 97: 408 – 412

    Article  PubMed  Google Scholar 

  • Wyllie AH, Kerr JFR, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68: 251 – 305

    Article  PubMed  CAS  Google Scholar 

  • Yamatsuji T, Matsui T, Okamoto T, Komatsuzaki K, Takeda S, Fukumoto H, Iwatsubo T, Suzuki N, Asami-Odaka A, Ireland S, Kinane B, Giambarella U, Nishimoto I (1996) G-protein-mediated neuronal DNA fragmentation induced by familial Alzheimer’s disease-associated mutants of APP. Science 272: 1349 – 1352

    Article  PubMed  CAS  Google Scholar 

  • Yo YH, Fortini ME (1999) Apopototic activities of wild-type and Alzheimer’s disease related mutant presenilins in Drosopihla melanogaster. J Cell Biol 146: 1351 – 1364

    Article  Google Scholar 

  • Zhang ZH, Hartmann H, Do VM (1998) Destabilization of β-catenin by mutations in presenilin-I potentiates neuronal apoptosis. Nature 395: 698 – 702

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Neuroimmunology, Brain Research Institute, University of Vienna School of Medicine, Vienna, Austria

    C. Stadelmann

  2. Institute of Neuropathology, Charité, Campus Virchow Klinikum, Berlin, Germany

    C. Stadelmann

  3. Ludwig Boltzmann Institute of Clinical, Psychiatric Hospital/B-Building, Baumgartner Hoehe 1, A-1140, Vienna, Austria

    Prof. Dr. K. A. Jellinger

Authors
  1. Prof. Dr. K. A. Jellinger
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  2. C. Stadelmann
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Editor information

Editors and Affiliations

  1. Ludwig-Boltzmann-Institut für Klinische Neurobiologie, Wien, Österreich

    K. Jellinger

  2. Universitätsklinik für Neurologie, Graz, Österreich

    R. Schmidt

  3. JSW-Forschungslabor, Graz, Österreich

    M. Windisch

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Dedicated to the memory of Herny M. Wisniewski who died on September 5, 1999.

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© 2000 Springer-Verlag

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Jellinger, K.A., Stadelmann, C. (2000). Mechanisms of cell death in neurodegenerative disorders. In: Jellinger, K., Schmidt, R., Windisch, M. (eds) Advances in Dementia Research. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6781-6_13

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  • DOI: https://doi.org/10.1007/978-3-7091-6781-6_13

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-211-83512-8

  • Online ISBN: 978-3-7091-6781-6

  • eBook Packages: Springer Book Archive

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