Severe neuronal losses with age in the parietal cortex and ventrobasal thalamus of mice transgenic for the human NF-L neurofilament protein.
Transgenic mice expressing human light neurofilament protein (NF-L) display early perikaryal accumulations of disarrayed neurofilaments in layers II/III of the parietal cortex and in the ventrobasal complex of thalamus. This cytoskeletal abnormality, reflected by strong NF-L immunoreactivity, is transient in the developing cortex but persists until old age in the thalamus. To investigate whether it leads to neuronal death, the unbiased cell counting method of the dissector was applied to the parietal cortex and the thalamus of normal and transgenic mice at various postnatal (P10, P20, P90) and advanced ages (14-18 months). Similar data were also obtained from the primary visual cortex free of NF-L accumulation. Compared with normal, the total number of neurons in the parietal (but not occipital) cortex of transgenic mice showed little change during the postnatal period, but decreased markedly with old age, particularly in layers II/III. Severe neuronal loss was also documented in the thalamic ventrobasal complex of aged transgenic mice. The delayed neuronal death in the parietal cortex, occurring long after recovery from the NF-L accumulations, was suggestive of a combination of deleterious factors, including the early overproduction of neurofilament protein and subsequent loss of afferent input from the affected somatosensory thalamic nuclei. Furthermore, strong accumulation of lipofuscin in the neurons of aged transgenic mice suggested that oxidative stress partakes in the mechanisms through which NF-L overproduction compromises neuronal viability.
Ma
D
D
Département de pathologie et biologie cellulaire and Centre de recherche en sciences neurologiques, Université de Montréal, Québec, Canada.
Descarries
L
L
Micheva
K D
KD
Lepage
Y
Y
Julien
J P
JP
Doucet
G
G
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death; D002552:Cerebral Ventricles / Q000033:anatomy & histology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic / Q000033:anatomy & histology* / Q000378:metabolism; D016900:Neurofilament Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009778:Occipital Lobe / Q000473:pathology; D009929:Organ Size / Q000502:physiology; D010296:Parietal Lobe / Q000378:metabolism / Q000473:pathology*; D013045:Species Specificity; D013787:Thalamic Nuclei / Q000378:metabolism / Q000473:pathology*; D014793:Visual Cortex / Q000378:metabolism / Q000473:pathology
D016900:Neurofilament Proteins; C044882:neurofilament protein L