title: PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice.
abstract: 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.
authors.affiliation: Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA.
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Gui-Qui
authors.initials: GQ
authors.lastname: Yu
authors.forename: Guofen
authors.initials: G
authors.lastname: Zhu
authors.forename: Viktor N
authors.initials: VN
authors.lastname: Kharazia
authors.forename: J Peter
authors.initials: JP
authors.lastname: Paredes
authors.forename: Wesley S
authors.initials: WS
authors.lastname: Chang
authors.forename: Jason K
authors.initials: JK
authors.lastname: Deitchman
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
mesh_terms: 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*
chemical_list: D000682:Amyloid; D051744:Protein Kinase C-epsilon; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes