S. Takauchi et K. Miyoshi, CYTOSKELETAL CHANGES IN RAT CORTICAL-NEURONS INDUCED BY LONG-TERM INTRAVENTRICULAR INFUSION OF LEUPEPTIN, Acta Neuropathologica, 89(1), 1995, pp. 8-16
Neurofibrillary tangles (NFTs), which are composed of paired helical f
ilament (PHF)-like filaments, were induced by the long-term intraventr
icular infusion of leupeptin, a potent protease inhibitor. The fibrils
composing the NFTs were 20 nm in maximal width and had periodic const
rictions at 40-nm intervals. They were identical to the PHF that had b
een found in aged rat neurons. Dystrophic axons filled with mainly tub
ular structures were also abundantly found in the parietal and tempora
l isocortices, which were not affected in the acute or subacute phases
of leupeptin treatment. An immunohistochemical study using antibodies
related to the neuronal cytoskeleton showed that neuronal cytoskeleta
l changes accompanying ubiquitination occurred in dystrophic axons dis
tributed widely in the isocortex as well as the hippocampal formation.
The present findings suggest that long-term administration of leupept
in accelerates the neuronal ageing process in rats and causes other ne
uronal changes: NFT formation, such as seen in the aged brain or in ne
urodegenerative diseases including Alzheimer's disease, in addition to
accumulation of lipofuscin granules and degeneration of neuronal proc
esses. In other words, some disturbance of the balance between proteas
es and their inhibitors may play an important role in the neuronal age
ing process, and some regulatory intervention in the intraneuronal pro
tease activity may provide a new therapeutic strategy for the neurodeg
enerative diseases.