Inhibition of neprilysin by thiorphan (i.c.v.) causes an accumulation of amyloid beta and impairment of learning and memory.

An accumulation of amyloid beta peptide (Abeta) due to an imbalance between anabolism and catabolism triggers Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in the catabolism of Abeta in brain. We investigated whether rats continuously infused with thiorphan, a specific inhibitor for neprilysin, into the cerebral ventricle cause cognitive dysfunction, with an accumulation of Abeta in the brain. Thiorphan-infused rats displayed significant cognitive dysfunction in the ability to discriminate in the object recognition test and spatial memory in the water maze test, but not in other hippocampus-dependent learning and memory tasks. Thiorphan infusion also elevated the Abeta40 level in the insoluble fraction of the cerebral cortex, but not that of the hippocampus. There was no significant difference in the nicotine-stimulated release of acetylcholine in the hippocampus between vehicle- and thiorphan-infused rats. These results indicate that continuous infusion of thiorphan into the cerebral ventricle causes cognitive dysfunction by raising the level of Abeta in the cerebral cortex, and suggest that a reduction of neprilysin activity contribute to the deposition of Abeta and development of AD.