NERVE GROWTH-FACTOR STRATEGY AND PREPARAT ION OF ANIMAL-MODEL FOR ALZHEIMER-TYPE SENILE DEMENTIA

Nerve growth factor (NGF) plays an important role in the survival and maintenance of cholinergic neurons in the central nervous system. In s enile dementia of the Alzheimer type (SDAT), learning and memory are i mpaired by the loss of neurons in the magnocellular cholinergic neuron al system. It is, therefore, of interest to investigate the role of NG F in this degenerative disorder. Since NGF does not cross the blood-br ain barrier and is easily metabolized by peptidases when administered peripherally, it can be used for medical treatment only when directly injected into the brain. We tried to develop drugs which could be take n orally and stimulate the NGF synthesis in the brain. In addition, we attempted to develop a SDAT animal model using osmotic minipump to in fuse beta-amyloid protein into cerebral ventricle, since there are no SDAT model animals accompanied with various pathophysiological changes . We demonstrate here that the oral administration of propentofylline, idebenone and trimethylquinone derivative, potent in vitro NGF synthe sis stimulators, induced the increase in NGF protein and mRNA, and in choline acetyltransferase activity, in basal forebrain-lesioned and ag ed rats, but not in intact young rats. These drugs also ameliorated th e behavioral deficits in habituation, water maze, and passive avoidanc e tasks in these animals. These results suggest that these drugs stimu lated NGF synthesis in vivo and ameliorated the behavioral deficits wh ich were accompanied with the reduced choline acetyltransferase activi ty in the basal forebrain-lesioned and aged rats. In terms of the SDAT animal model, the performance of the water maze and passive avoidance tasks was impaired and choline acetyltransferase activity significant ly decreased in beta-amyloid protein-treated rats. Histochemical resul ts showed the deposition of beta-amyloid protein in the cortex and hip pocampus and atrophy and loss of hippocampal neurons. These results su ggest that the deposition of beta-amyloid protein in the brain is rela ted to the impairment of learning and cholinergic neuronal degeneratio n, and that beta-amyloid protein-treated rats could be an animal model for SADT and used for the screening of drugs for SDAT.