Inhibition of neprilysin by infusion of thiorphan into the hippocampus causes an accumulation of amyloid β and impairment of learning and memory

An imbalance between anabolism and catabolism causes an accumulation of amyloid beta-peptide (A beta), which is a proposed trigger of the onset of Alzheimer's disease. Neprilysin is a rate-limiting peptidase that participates in the catabolism of A beta in the brain. We examined whether rats continuously infused with thiorphan, a specific neprilysin inhibitor, into the hippocampus develop cognitive impairments through accumulation of A beta. Thiorphan infusion elevated hippocampal A beta 40 and A beta 42 levels in the insoluble but not the soluble fraction. Thiorphan-infused rats displayed cognitive impairments in the ability to discriminate in the object recognition test, associative learning in the conditioned fear learning test, and spatial memory in the water maze test, tasks that depend on the hippocampus. These cognitive abilities in the battery of behavioral tasks inversely correlated with insoluble A beta contents in the hippocampus. The nicotine-stimulated release of acetylcholine in the hippocampus of thiorphan-infused rats was significantly lower than that in vehicle-infused rats. These results indicate that continuous infusion of thiorphan into the hippocampus causes cognitive dysfunction and reduces cholinergic activity by raising the level of A beta in the hippocampus and suggest that a reduction of neprilysin activity contributes to the deposition of A beta and development of Alzheimer's disease.