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.
Footnotes
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This work was supported, in part, by grants-in-aid for scientific research from the Japan Society for the Promotion of Science (14370031, 15922139, 16922036, and 17390018), Scientific Research on Priority Areas “Elucidation of Glia-Neuron Network Mediated Information Processing Systems” (16047214), and Research on Pathomechanisms of Brain Disorders (17025046) from the Ministry of Education, Culture, Sports, Science and Technology; by funds from Integrated Molecular Medicine for Neuronal and Neoplastic Disorders (21st Century Center of Excellence program), the Japan Brain Foundation, and the Mitsubishi Pharma Research Foundation; and by an Smoking Research Foundation Grant for Biomedical Research.
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L.-B.Z. and A.M. contributed equally to this work.
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doi:10.1124/jpet.105.095687.
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ABBREVIATIONS: Aβ, amyloid β-peptide; APP; amyloid precursor protein, ACh, acetylcholine; ELISA, enzyme-linked immunosorbent assay; ANOVA, analysis of variance; Veh/SAL, vehicle + saline; Thio/SAL, thiorphan + saline; Thio/NAL, thiorphan + naloxone.
- Received September 15, 2005.
- Accepted December 23, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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