CYTOSKELETAL CHANGES IN RAT CORTICAL-NEURONS INDUCED BY LONG-TERM INTRAVENTRICULAR INFUSION OF LEUPEPTIN

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.