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/I II of the parietal cortex and in the ventrobasal complex of thalamus. This cytoskeletal abnormality, reflected by strong NF-L immunoreactivity, is tra nsient in the developing cortex but persists until old age in the thalamus. To investigate whether it leads to neuronal death, the unbiased cell count ing method of the dissector was applied to the parietal cortex and the thal amus of normal and transgenic mice at various postnatal (P10, P20, P90) and advanced ages (14-18 months). Similar data were also obtained from the pri mary visual cortex free of NF-L accumulation. Compared with normal, the tot al number of neurons in the parietal (but not occipital) cortex of transgen ic mice showed little change during the postnatal period, but decreased mar kedly with old age, particularly in layers II/III. Severe neuronal loss was also documented in the thalamic ventrobasal complex of aged transgenic mic e. The delayed neuronal death in the parietal cortex, occurring long after recovery from the NF-L accumulations, was suggestive of a combination of de leterious factors, including the early overproduction of neurofilament prot ein and subsequent loss of afferent input from the affected somatosensory t halamic nuclei. Furthermore, strong accumulation of lipofuscin in the neuro ns of aged transgenic mice suggested that oxidative stress partakes in the mechanisms through which NF-L overproduction compromises neuronal viability . J. Comp. Neurol. 406:433-448, 1999. (C) 1999 Wiley-Liss, Inc.