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

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.