Journal of Neuroscience, Vol 14, 5603-5612, Copyright © 1994 by Society for Neuroscience
Age-associated and cell-type-specific neurofibrillary pathology in transgenic mice expressing the human midsized neurofilament subunit
JC Vickers, JH Morrison, VL Friedrich Jr, GA Elder, DP Perl, RN Katz and RA Lazzarini
Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029-6574.
Alterations in neurofilaments are a common occurrence in neurons of the
human nervous system during aging and diseases associated with aging. Such
pathologic changes may be attributed to species-specific properties of
human neurofilaments as well as cell-type-specific regulation of this
element of the cytoskeleton. The development of transgenic animals
containing human neurofilament subunits offers an opportunity to study the
effects of aging and other experimental conditions on the human-specific
form of these proteins in a rodent model. The present study shows that mice
from the transgenic line NF(M)27, which express the human midsized
neurofilament subunit at low levels (2-25% of the endogenous NF-M), develop
neurofilamentous accumulations in specific subgroups of neurons that are
age dependent, affecting 78% of transgenic mice over 12 months of age.
Similar accumulations do not occur in age-matched, wild-type littermates or
in 3-month-old transgenic mice. In 12-month-old transgenic mice, somatic
neurofilament accumulations resembling neurofibrillary tangles were present
predominantly in layers III and V of the neocortex, as well as in select
subpopulations of subcortical neurons. Intraperikaryal, spherical
neurofilamentous accumulations were particularly abundant in cell bodies in
layer II of the neocortex, and neurofilament-containing distentions of
Purkinje cell proximal axons occurred in the cerebellum. These pathological
accumulations contained mouse as well as human NF subunits, but could be
distinguished by their content of phosphorylation-dependent NF epitopes.
These cytoskeletal alterations closely resemble the cell-type-specific
alterations in neurofilaments that occur during normal human aging and in
diseases associated with aging, indicating that these transgenic animals
may serve as models of some aspects of the pathologic features of human
neurodegenerative diseases.
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