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

Proc Natl Acad Sci U S A. 2006 May 23;103(21):8215-20. doi: 10.1073/pnas.0509725103. Epub 2006 May 12.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry*
  • Animals
  • Aspartic Acid Endopeptidases / metabolism*
  • Brain / metabolism
  • Endothelin-Converting Enzymes
  • Endothelium, Vascular / cytology
  • Gliosis / pathology
  • Hippocampus / metabolism
  • Humans
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurodegenerative Diseases / pathology
  • Neurons / metabolism
  • Phosphorylation
  • Protein Kinase C-epsilon / physiology*


  • Amyloid
  • Protein Kinase C-epsilon
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • Endothelin-Converting Enzymes