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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 28, 2005; DOI: 10.1124/jpet.105.095687

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Received for publication September 27, 2005.
Revised December 23, 2005.
Accepted for publication December 23, 2005.

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

Li-Bo Zou 1, Akihiro Mouri 2, Nobuhisa Iwata 3, Takaomi C Saido 3, Dayong Wang 2, Min-Wei Wang 1, Hiroyuki Mizoguchi 2, Yukihiro Noda 4, Toshitaka Nabeshima 2*

1 Shenyang Pharmaceutical University 2 Nagoya University Graduate School of Medicine 3 RIKEN Brain Science Institute 4 Nagoya University Graduate School of Medicine and Meijo University

* Address correspondence to: E-mail: tnabeshi{at}med.nagoya-u.ac.jp

Abstract

An imbalance between anabolism and catabolism causes an accumulation of amyloid {beta} peptide (A{beta}), which triggers the onset of Alzheimers disease (AD). Neprilysin is a rate-limiting peptidase, which 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 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 which depend on the hippocampus. These cognitive abilities in the battery of behavioral tasks reversely 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.


Key words: Alzheimers disease, amyloid beta, cognitive dysfunction, neprilysin, rat, thiorphan


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S. S. El-Amouri, H. Zhu, J. Yu, R. Marr, I. M. Verma, and M. S. Kindy
Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease
Am. J. Pathol., May 1, 2008; 172(5): 1342 - 1354.
[Abstract] [Full Text] [PDF]


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