Inhibition of Neprilysin by Infusion of Thiorphan into the Hippocampus Causes an Accumulation of Amyloid β and Impairment of Learning and Memory
- 28 December 2005
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 317 (1), 334-340
- https://doi.org/10.1124/jpet.105.095687
Abstract
An imbalance between anabolism and catabolism causes an accumulation of amyloid β-peptide (Aβ), which is a proposed trigger of the onset of Alzheimer's disease. Neprilysin is a rate-limiting peptidase that participates in the catabolism of Aβ in the brain. We examined whether rats continuously infused with thiorphan, a specific neprilysin inhibitor, into the hippocampus develop cognitive impairments through accumulation of Aβ. Thiorphan infusion elevated hippocampal Aβ40 and Aβ42 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 Aβ 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 Aβ in the hippocampus and suggest that a reduction of neprilysin activity contributes to the deposition of Aβ and development of Alzheimer's disease.Keywords
This publication has 35 references indexed in Scilit:
- The role of the hippocampus in object recognition in rats: Examination of the influence of task parameters and lesion sizeBehavioural Brain Research, 2006
- Metabolism of amyloid-β peptide and Alzheimer's diseasePharmacology & Therapeutics, 2005
- A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascadeProceedings of the National Academy of Sciences of the United States of America, 2004
- Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivoProceedings of the National Academy of Sciences of the United States of America, 2003
- Alzheimer's Disease β-Amyloid Peptide Is Increased in Mice Deficient in Endothelin-converting EnzymePublished by Elsevier BV ,2003
- The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to TherapeuticsScience, 2002
- Aβ-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Aβ pathologyNeuroscience Research, 2002
- Impairments of long-term potentiation in hippocampal slices of β-amyloid-infused ratsEuropean Journal of Pharmacology, 1999
- Neurotoxic lesions of the perirhinal cortex do not mimic the behavioural effects of fornix transection in the ratBehavioural Brain Research, 1996
- Opiate Antagonists Improve Spatial MemoryScience, 1983