Thiorphan-induced neprilysin inhibition raises amyloid β levels in rabbit cortex and cerebrospinal fluid

• Published in: Neuroscience letters Vol. 350; no. 3; pp. 178 - 180
• Main Authors: Newell, Amanda J., Sue, Lucia I., Scott, Sarah, Rauschkolb, Paula K., Walker, Douglas G., Potter, Pamela E., Beach, Thomas G.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 30.10.2003; Elsevier
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid β; Animal model; Animals; Biological and medical sciences; Brain Chemistry - drug effects; Cerebral cortex; Cerebral Cortex - chemistry; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enzyme-Linked Immunosorbent Assay; Immunoblotting; Immunohistochemistry; Injections, Intraventricular; Medical sciences; Neprilysin; Neprilysin - drug effects; Neurology; Peptide Fragments; Protease Inhibitors - administration & dosage; Protease Inhibitors - pharmacology; Rabbits; Thiorphan; Thiorphan - administration & dosage; Thiorphan - pharmacology; Rabbits; Animal model; Cerebral cortex; Amyloid β; Neprilysin; Thiorphan; Alzheimer's disease; Cerebellum; Alzheimer disease; Central nervous system; Rabbit; Metalloendopeptidases; Cerebrospinal fluid; Degenerative disease; Nervous system diseases; Enzyme; Enzyme inhibitor; Lagomorpha; Cerebral disorder; Peptidases; Vertebrata; Mammalia; β Amyloid protein; Central nervous system disease; Hydrolases; Brain (vertebrata)
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/S0304-3940(03)00902-9

Studies on the pathogenesis of Alzheimer's disease (AD) suggest overproduction of amyloid β (Aβ) may not be the only pathogenic route to AD. Decreased degradation of Aβ is another possible disease mechanism. Neprilysin is a neutral endopeptidase that has been proposed to be the major enzyme responsible for Aβ degradation. Studies have reported correlations between Aβ deposition and neprilysin activity in the human brain. This study shows that intracerebroventricular infusion of thiorphan, a neprilysin inhibitor, raises cortical and cerebrospinal fluid (CSF) Aβ concentrations in rabbits. Rabbits treated with thiorphan for 5 days had levels of CSF and cortical Aβ40 that were 147 and 142% of the control group, respectively. Results for Aβ42 showed a similar trend. The results indicate that age-related decreases of neprilysin could lead to increased brain concentrations of Aβ, plaque formation, and AD.