Inhibition of neprilysin by infusion of thiorphan into the hippocampus causes an accumulation of amyloid Beta and impairment of learning and memory.
An imbalance between anabolism and catabolism causes an accumulation of amyloid beta-peptide (Abeta), which is a proposed trigger of the onset of Alzheimer's disease. Neprilysin is a rate-limiting peptidase that participates in the catabolism of Abeta in the brain. We examined whether rats continuously infused with thiorphan, a specific neprilysin inhibitor, into the hippocampus develop cognitive impairments through accumulation of Abeta. Thiorphan infusion elevated hippocampal Abeta40 and Abeta42 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 Abeta 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 Abeta in the hippocampus and suggest that a reduction of neprilysin activity contributes to the deposition of Abeta and development of Alzheimer's disease.
Zou
Li-Bo
LB
Department of Pharmacology, School of Pharmacy, Shenyang Pharmaceutical University, China.
Mouri
Akihiro
A
Iwata
Nobuhisa
N
Saido
Takaomi C
TC
Wang
Dayong
D
Wang
Min-Wei
MW
Mizoguchi
Hiroyuki
H
Noda
Yukihiro
Y
Nabeshima
Toshitaka
T
D000109:Acetylcholine / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007263:Infusions, Parenteral; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009538:Nicotine / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015244:Thiorphan / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D009538:Nicotine; D015244:Thiorphan; D015260:Neprilysin; D000109:Acetylcholine