Epigenetic and Pharmacological Regulationof the Amyloid-Degrading Enzyme Neprilysin Resultsin Modulation of Cognitive Functions in Mammals

摘要

The present work reports an experimental testing ofa hypothesis that epigenetic and pharmacological regulation of the activity of amyloid-degrading enzymeneprilysin (NEP) results in changes in the plasticity ofthe nervous system and affects cognitive functions. Itwas found that prenatal hypoxia or prolonged administration to rats of a neprilysin inhibitor phosphoramidon led to a decrease in the number of labile spines inthe cortical regions of the brain and to deterioration oftheir short-term working memory tested in a radialmaze. On the contrary, injections to rats with reducedNEP activity (after prenatal hypoxia) of an inhibitor ofhistone deacetylase, sodium valproate, led to anenhanced NEP activity, increased number of labilespines and improved memory. The data obtainedallowed us to conclude that the decrease in the activityof amyloid-degrading enzymes, in particular of NEP,is accompanied by a reduced number of labile intraneuronal contacts which might be one of the reasonsof cognitive decline caused by pathological development or ageing. This decline can be compensated byregulating expression and activity of amyloid-degrading enzymes.