Neurofilament-rich intraneuronal inclusions exacerbate neurodegenerative sequelae of brain trauma in NFH/LacZ transgenic mice

被引:14
作者
Galvin, JE [1 ]
Nakamura, M
McIntosh, TK
Saatman, KE
Sampathu, D
Raghupathi, R
Lee, VMY
Trojanowski, JQ
机构
[1] Med Coll Penn & Hahnemann Univ, Dept Neurol, Philadelphia, PA 19102 USA
[2] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA
关键词
neuronal cytoplasmic inclusions; Lewy bodies; neurofilament; apoptosis; traumatic brain injury; transgenic mice; Parkinson's disease; neurodegeneration;
D O I
10.1006/exnr.2000.7461
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Several neurodegenerative disorders are characterized by filamentous inclusions in neurons that selectively degenerate. The role these inclusions play in neuron degeneration is unclear, but this issue can, be investigated experimentally in relevant animal models. The NFH/LacZ transgenic (TG) mice overexpress the high-molecular-weight neurofilament (NF) subunit (NFH) fused to beta-galactosidase, and these hybrid proteins aggregate into NF-rich, filamentous neuronal cytoplasmic inclusions (NCIs) that have been implicated in the progressive, age-dependent degeneration in subsets of affected neurons. Thus, these TG mice recapitulate some of the key pathology of neurodegenerative disorders with intraneuronal inclusions. To determine if the NCIs compromise neuron survival following traumatic brain injury (TBI), 3- to 6-month old TG and wild-type (WT) mice were subjected to TBI or sham injury. At 2 weeks post-TBI, the TG group showed increased TUNEL staining and activated caspase-3 immunoreactivity in cells of cerebral cortex, adjacent white matter, and hippocampus underlying the injury site, relative to control mice, but this labeling decreased at 4 weeks and was minimal thereafter. Compared to control mice, by 8 weeks postinjury, the TG mice showed a marked decrease in neuron density and increased gliosis in the hippocampal dentate gyrus and CA3 region as well as in the lateral thalamus, while the few remaining CA3 neurons exhibited cytoskeletal alterations, decreased synaptic protein immunoreactivity, and dissolution of NCIs. The more profound long-term neurodegenerative sequelae of TBI in the NFH/LacZ mice compared to WT mice suggest that the presence of intraneuronal inclusions may impair the recovery and long-term viability of injured neurons. (C) 2000 Academic Press.
引用
收藏
页码:77 / 89
页数:13
相关论文
共 76 条
  • [1] EXPRESSION PATTERNS OF BETA-AMYLOID PRECURSOR PROTEIN (BETA-APP) IN NEURAL AND NONNEURAL HUMAN TISSUES FROM ALZHEIMERS-DISEASE AND CONTROL SUBJECTS
    ARAI, H
    LEE, VMY
    MESSINGER, ML
    GREENBERG, BD
    LOWERY, DE
    TROJANOWSKI, JQ
    [J]. ANNALS OF NEUROLOGY, 1991, 30 (05) : 686 - 693
  • [2] Baba M, 1998, AM J PATHOL, V152, P879
  • [3] TROPHISM, TRANSPLANTATION, AND ANIMAL-MODELS OF PARKINSONS-DISEASE
    BANKIEWICZ, K
    MANDEL, RJ
    SOFRONIEW, MV
    [J]. EXPERIMENTAL NEUROLOGY, 1993, 124 (01) : 140 - 149
  • [4] DIFFERENTIAL LOCALIZATION OF MAP-2 AND TAU IN MAMMALIAN NEURONS INSITU
    BINDER, LI
    FRANKFURTER, A
    REBHUN, LI
    [J]. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1986, 466 : 145 - 166
  • [5] Brinkley B R, 1980, Int Rev Cytol, V63, P59, DOI 10.1016/S0074-7696(08)61757-X
  • [6] Programmed cell death: Does it play a role in Parkinson's disease?
    Burke, RE
    Kholodilov, NG
    [J]. ANNALS OF NEUROLOGY, 1998, 44 (03) : S126 - S133
  • [7] Chen J, 1998, J NEUROSCI, V18, P4914
  • [8] Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury
    Cheng, Y
    Deshmukh, M
    D'Costa, A
    Demaro, JA
    Gidday, JM
    Shah, A
    Sun, YL
    Jacquin, MF
    Johnson, EM
    Holtzman, DM
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (09) : 1992 - 1999
  • [9] Clark RSB, 1997, J NEUROSCI, V17, P9172
  • [10] Delayed, selective neuronal death following experimental cortical impact injury in rats: Possible role in memory deficits
    Colicos, MA
    Dixon, CE
    Dash, PK
    [J]. BRAIN RESEARCH, 1996, 739 (1-2) : 111 - 119