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

Deposition of plaques containing amyloid beta (A beta) peptides is a neuropathological hallmark of Alzheimer's disease (AD). Here we demonstrate that neuronal overexpression of the epsilon isozyme of PKC decreases A beta 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/PKCE doubly transgenic mice had decreased A beta levels but showed no evidence for altered cleavage of APP. Instead, PKC epsilon overexpression selectively increased the activity of endothelin-converting enzyme, which degrades A beta. The activities of other A beta-clegrading enzymes, insulin degrading enzyme and neprilysin, were unchanged. These results indicate that increased neuronal PKC epsilon activity can promote A beta clearance and reduce AD neuropathology through increased endothelin-converting enzyme activity.