Temporal profiles of neuronal degeneration, glial proliferation, and cell death in hNFL(+/+) and NFL(-/-) mice.
Neurofilament (NF) aggregate formation within motor neurons is a pathological hallmark of both the sporadic and familial forms of amyotrophic lateral sclerosis (ALS). The relationship between aggregate formation and both microglial and astrocytic proliferation, as well as additional neuropathological features of ALS, is unknown. To examine this, we have used transgenic mice that develop NF aggregates, through either a lack of the low-molecular-weight NF subunit [NFL (-/-)] or the overexpression of human NFL [hNFL (+/+)]. Transgenic and wild-type C57bl/6 mice were examined from 1 month to 18 months of age, and the temporal pattern of motor neuron degeneration, microglial and astrocytic proliferation, and heat shock protein-70 (HSP-70) expression characterized. We observed three overlapping phases in both transgenic mice, including transient aggregate formation, reactive microgliosis, and progressive motor neuron loss. However, only NFL (-/-) mice demonstrated significant astrogliosis and HSP-70 upregulation in both motor neurons and astrocytes. These in vivo models suggest that the development of NF aggregates in motor neurons leads to motor neuron death, but that the interaction between the degenerating motor neurons and the adjacent non-neuronal cells may differ significantly depending on the etiology of the NF aggregate itself.
McLean
Jesse R
JR
Department of Pathology, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada.
Sanelli
Teresa R
TR
Leystra-Lantz
Cheryl
C
He
Bei Ping
BP
Strong
Michael J
MJ
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016900:Neurofilament Proteins / Q000235:genetics*; D013997:Time Factors
D018840:HSP70 Heat-Shock Proteins; D016900:Neurofilament Proteins; C044882:neurofilament protein L; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases