PKCε increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice

Abstract

Deposition of plaques containing amyloid β (Aβ) peptides is a neuropathological hallmark of Alzheimer9s disease (AD). Here we demonstrate that neuronal overexpression of the ε isozyme of PKC decreases Aβ levels, plaque burden, and plaque-associated neuritic dystrophy and reactive astrocytosis in transgenic mice expressing familial AD-mutant forms of the human amyloid precursor protein (APP). Compared with APP singly transgenic mice, APP/PKCε doubly transgenic mice had decreased Aβ levels but showed no evidence for altered cleavage of APP. Instead, PKCε overexpression selectively increased the activity of endothelin-converting enzyme, which degrades Aβ. The activities of other Aβ-degrading enzymes, insulin degrading enzyme and neprilysin, were unchanged. These results indicate that increased neuronal PKCε activity can promote Aβ clearance and reduce AD neuropathology through increased endothelin-converting enzyme activity.