PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice.
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.
Choi
Doo-Sup
DS
Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA.
Wang
Dan
D
Yu
Gui-Qui
GQ
Zhu
Guofen
G
Kharazia
Viktor N
VN
Paredes
J Peter
JP
Chang
Wesley S
WS
Deitchman
Jason K
JK
Mucke
Lennart
L
Messing
Robert O
RO
D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000166:cytology; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000502:physiology*
D000682:Amyloid; D051744:Protein Kinase C-epsilon; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes