Neurofilament-rich intraneuronal inclusions exacerbate neurodegenerative sequelae of brain trauma in NFH/LacZ transgenic mice.
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.
Galvin
J E
JE
Department of Neurology, MCP Hahnemann University, Philadelphia, Pennsylvania, USA.
Nakamura
M
M
McIntosh
T K
TK
Saatman
K E
KE
Sampathu
D
D
Raghupathi
R
R
Lee
V M
VM
Trojanowski
J Q
JQ
D000818:Animals; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D003599:Cytoskeleton / Q000648:ultrastructure; D002479:Inclusion Bodies / Q000502:physiology*; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D016900:Neurofilament Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology*
D016900:Neurofilament Proteins; C051774:neurofilament protein H