• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Jan 1997; 150(1): 119–131.
PMCID: PMC1858540

Apoptotic-like changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons.

Abstract

In Parkinson's disease and other Lewy-body-associated disorders, the substantia nigra pars compacta undergoes degeneration, but the mechanism of cell death has not been previously described. The substantia nigra of normal and Alzheimer's disease cases were compared with substantia nigra from patients with Lewy-body-associated disorders (Parkinson's disease, concomitant Alzheimer's/Parkinson's disease, and diffuse Lewy body disease) using in situ end labeling to detect fragmented DNA. In situ end-labeled neurons demonstrated changes resembling apoptosis: nuclear condensation, chromatin fragmentation, and formation of apoptotic-like bodies. Ultrastructural analysis confirmed nuclear condensation and formation of apoptotic-like bodies. Apoptotic-like changes were seen in the substantia nigra of both normal and diseased cases; concomitant Alzheimer's/Parkinson's disease and diffuse Lewy body disease cases had significantly higher amounts of apoptotic-like changes than normal controls or Alzheimer patients. The finding of neuronal death by apoptosis may have relevance for the development of new treatment strategies for Parkinson's disease and related disorders.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (3.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Gibb WR, Lees AJ. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1991 May;54(5):388–396. [PMC free article] [PubMed]
  • Gibb WR. Neuropathology in movement disorders. J Neurol Neurosurg Psychiatry. 1989 Jun;Suppl:55–67. [PMC free article] [PubMed]
  • Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain. 1991 Oct;114(Pt 5):2283–2301. [PubMed]
  • Boller F, Mizutani T, Roessmann U, Gambetti P. Parkinson disease, dementia, and Alzheimer disease: clinicopathological correlations. Ann Neurol. 1980 Apr;7(4):329–335. [PubMed]
  • Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK, de la Monte S, Norenberg MD, Schneck SA. Diffuse Lewy body disease and progressive dementia. Neurology. 1988 Oct;38(10):1520–1528. [PubMed]
  • Morris JC, Drazner M, Fulling K, Grant EA, Goldring J. Clinical and pathological aspects of parkinsonism in Alzheimer's disease. A role for extranigral factors? Arch Neurol. 1989 Jun;46(6):651–657. [PubMed]
  • Perry RH, Irving D, Blessed G, Fairbairn A, Perry EK. Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci. 1990 Feb;95(2):119–139. [PubMed]
  • Ince P, Irving D, MacArthur F, Perry RH. Quantitative neuropathological study of Alzheimer-type pathology in the hippocampus: comparison of senile dementia of Alzheimer type, senile dementia of Lewy body type, Parkinson's disease and non-demented elderly control patients. J Neurol Sci. 1991 Dec;106(2):142–152. [PubMed]
  • Lennox G, Lowe J, Byrne EJ, Landon M, Mayer RJ, Godwin-Austen RB. Diffuse Lewy body disease. Lancet. 1989 Feb 11;1(8633):323–324. [PubMed]
  • Galloway PG, Bergeron C, Perry G. The presence of tau distinguishes Lewy bodies of diffuse Lewy body disease from those of idiopathic Parkinson disease. Neurosci Lett. 1989 May 22;100(1-3):6–10. [PubMed]
  • Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, Thal L, Pay MM, Hofstetter R, Klauber M, et al. The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 1990 Jan;40(1):1–8. [PubMed]
  • Förstl H, Burns A, Luthert P, Cairns N, Levy R. The Lewy-body variant of Alzheimer's disease. Clinical and pathological findings. Br J Psychiatry. 1993 Mar;162:385–392. [PubMed]
  • Dickson DW, Crystal H, Mattiace LA, Kress Y, Schwagerl A, Ksiezak-Reding H, Davies P, Yen SH. Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques. Acta Neuropathol. 1989;78(6):572–584. [PubMed]
  • Buja LM, Eigenbrodt ML, Eigenbrodt EH. Apoptosis and necrosis. Basic types and mechanisms of cell death. Arch Pathol Lab Med. 1993 Dec;117(12):1208–1214. [PubMed]
  • Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl) 1990;181(3):195–213. [PubMed]
  • Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. [PMC free article] [PubMed]
  • Macaya A, Munell F, Gubits RM, Burke RE. Apoptosis in substantia nigra following developmental striatal excitotoxic injury. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8117–8121. [PMC free article] [PubMed]
  • Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995 Jan;146(1):3–15. [PMC free article] [PubMed]
  • Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. [PMC free article] [PubMed]
  • Wijsman JH, Jonker RR, Keijzer R, van de Velde CJ, Cornelisse CJ, van Dierendonck JH. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA. J Histochem Cytochem. 1993 Jan;41(1):7–12. [PubMed]
  • Su JH, Anderson AJ, Cummings BJ, Cotman CW. Immunohistochemical evidence for apoptosis in Alzheimer's disease. Neuroreport. 1994 Dec 20;5(18):2529–2533. [PubMed]
  • Lassmann H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, Jellinger K, Wisniewski HM. Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ. Acta Neuropathol. 1995;89(1):35–41. [PubMed]
  • Dragunow M, Faull RL, Lawlor P, Beilharz EJ, Singleton K, Walker EB, Mee E. In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Neuroreport. 1995 May 9;6(7):1053–1057. [PubMed]
  • Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE. Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci. 1995 May;15(5 Pt 2):3775–3787. [PubMed]
  • Yoshiyama Y, Yamada T, Asanuma K, Asahi T. Apoptosis related antigen, Le(Y) and nick-end labeling are positive in spinal motor neurons in amyotrophic lateral sclerosis. Acta Neuropathol. 1994;88(3):207–211. [PubMed]
  • Troost D, Aten J, Morsink F, de Jong JM. Apoptosis in amyotrophic lateral sclerosis is not restricted to motor neurons. Bcl-2 expression is increased in unaffected post-central gyrus. Neuropathol Appl Neurobiol. 1995 Dec;21(6):498–504. [PubMed]
  • Khachaturian ZS. Diagnosis of Alzheimer's disease. Arch Neurol. 1985 Nov;42(11):1097–1105. [PubMed]
  • Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. Arch Pathol Lab Med. 1993 Feb;117(2):132–144. [PubMed]
  • Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479–486. [PubMed]
  • Quinn NP, Husain FA. Parkinson's disease. Br Med J (Clin Res Ed) 1986 Aug 9;293(6543):379–382. [PMC free article] [PubMed]
  • Duvoisin RC, Golbe LI. Toward a definition of Parkinson's disease. Neurology. 1989 May;39(5):746–746. [PubMed]
  • Daniel SE, Lees AJ. Parkinson's Disease Society Brain Bank, London: overview and research. J Neural Transm Suppl. 1993;39:165–172. [PubMed]
  • Lippa CF, Smith TW, Swearer JM. Alzheimer's disease and Lewy body disease: a comparative clinicopathological study. Ann Neurol. 1994 Jan;35(1):81–88. [PubMed]
  • Gibb WR, Esiri MM, Lees AJ. Clinical and pathological features of diffuse cortical Lewy body disease (Lewy body dementia). Brain. 1987 Oct;110(Pt 5):1131–1153. [PubMed]
  • Gibb WR, Luthert PJ, Janota I, Lantos PL. Cortical Lewy body dementia: clinical features and classification. J Neurol Neurosurg Psychiatry. 1989 Feb;52(2):185–192. [PMC free article] [PubMed]
  • Kosaka K. Diffuse Lewy body disease in Japan. J Neurol. 1990 Jun;237(3):197–204. [PubMed]
  • Dickson DW, Ruan D, Crystal H, Mark MH, Davies P, Kress Y, Yen SH. Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology. 1991 Sep;41(9):1402–1409. [PubMed]
  • Wood KA, Dipasquale B, Youle RJ. In situ labeling of granule cells for apoptosis-associated DNA fragmentation reveals different mechanisms of cell loss in developing cerebellum. Neuron. 1993 Oct;11(4):621–632. [PubMed]
  • Searle J, Kerr JF, Bishop CJ. Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance. Pathol Annu. 1982;17(Pt 2):229–259. [PubMed]
  • Deckwerth TL, Johnson EM., Jr Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J Cell Biol. 1993 Dec;123(5):1207–1222. [PMC free article] [PubMed]
  • Ansari B, Coates PJ, Greenstein BD, Hall PA. In situ end-labelling detects DNA strand breaks in apoptosis and other physiological and pathological states. J Pathol. 1993 May;170(1):1–8. [PubMed]
  • Gold R, Schmied M, Giegerich G, Breitschopf H, Hartung HP, Toyka KV, Lassmann H. Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Invest. 1994 Aug;71(2):219–225. [PubMed]
  • Mundle SD, Raza A. The two in situ techniques do not differentiate between apoptosis and necrosis but rather reveal distinct patterns of DNA fragmentation in apoptosis. Lab Invest. 1995 May;72(5):611–613. [PubMed]
  • Hockenbery D. Defining apoptosis. Am J Pathol. 1995 Jan;146(1):16–19. [PMC free article] [PubMed]
  • O'Connor TM, Wyttenbach CR. Cell death in the embryonic chick spinal cord. J Cell Biol. 1974 Feb;60(2):448–459. [PMC free article] [PubMed]
  • Pilar G, Landmesser L. Ultrastructural differences during embryonic cell death in normal and peripherally deprived ciliary ganglia. J Cell Biol. 1976 Feb;68(2):339–356. [PMC free article] [PubMed]
  • McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology. 1988 Aug;38(8):1285–1291. [PubMed]
  • McGeer PL, Itagaki S, Akiyama H, McGeer EG. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol. 1988 Oct;24(4):574–576. [PubMed]
  • Bojinov S. Encephalitis with acute Parkinsonian syndrome and bilateral inflammatory necrosis of the substantia nigra. J Neurol Sci. 1971 Apr;12(4):383–415. [PubMed]
  • Mann DM, Yates PO, Marcyniuk B. Monoaminergic neurotransmitter systems in presenile Alzheimer's disease and in senile dementia of Alzheimer type. Clin Neuropathol. 1984 Sep-Oct;3(5):199–205. [PubMed]
  • Galli G, Fratelli M. Activation of apoptosis by serum deprivation in a teratocarcinoma cell line: inhibition by L-acetylcarnitine. Exp Cell Res. 1993 Jan;204(1):54–60. [PubMed]
  • Hartley A, Stone JM, Heron C, Cooper JM, Schapira AH. Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: relevance to Parkinson's disease. J Neurochem. 1994 Nov;63(5):1987–1990. [PubMed]
  • Petito CK, Roberts B. Effect of postmortem interval on in situ end-labeling of DNA oligonucleosomes. J Neuropathol Exp Neurol. 1995 Nov;54(6):761–765. [PubMed]
  • Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci. 1993 Nov;16(11):439–444. [PubMed]
  • Larsson BS. Interaction between chemicals and melanin. Pigment Cell Res. 1993 Jun;6(3):127–133. [PubMed]
  • Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem. 1990 Mar;54(3):823–827. [PubMed]
  • Ziv I, Melamed E, Nardi N, Luria D, Achiron A, Offen D, Barzilai A. Dopamine induces apoptosis-like cell death in cultured chick sympathetic neurons--a possible novel pathogenetic mechanism in Parkinson's disease. Neurosci Lett. 1994 Mar 28;170(1):136–140. [PubMed]
  • McConkey DJ, Hartzell P, Duddy SK, Håkansson H, Orrenius S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin kills immature thymocytes by Ca2+-mediated endonuclease activation. Science. 1988 Oct 14;242(4876):256–259. [PubMed]
  • Wolvetang EJ, Johnson KL, Krauer K, Ralph SJ, Linnane AW. Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett. 1994 Feb 14;339(1-2):40–44. [PubMed]
  • Ratan RR, Murphy TH, Baraban JM. Oxidative stress induces apoptosis in embryonic cortical neurons. J Neurochem. 1994 Jan;62(1):376–379. [PubMed]
  • Allsopp TE, Wyatt S, Paterson HF, Davies AM. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell. 1993 Apr 23;73(2):295–307. [PubMed]
  • Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, Pietra C, et al. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron. 1994 Oct;13(4):1017–1030. [PubMed]
  • Takeshima T, Johnston JM, Commissiong JW. Mesencephalic type 1 astrocytes rescue dopaminergic neurons from death induced by serum deprivation. J Neurosci. 1994 Aug;14(8):4769–4779. [PubMed]
  • Yan Q, Matheson C, Lopez OT. In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature. 1995 Jan 26;373(6512):341–344. [PubMed]
  • Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993 May 21;260(5111):1130–1132. [PubMed]
  • Beck KD, Valverde J, Alexi T, Poulsen K, Moffat B, Vandlen RA, Rosenthal A, Hefti F. Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature. 1995 Jan 26;373(6512):339–341. [PubMed]
  • Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature. 1995 Jan 26;373(6512):335–339. [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...