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Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen‐2) demonstrate excessive p53‐dependent apoptosis and neuronal loss
Author(s) -
Campbell William A.,
Yang Hongwei,
Zetterberg Henrik,
Baulac Stéphanie,
Sears Jacqueline A.,
Liu Tianming,
Wong Stephen T. C.,
Zhong Tao P.,
Xia Weiming
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03648.x
Subject(s) - gene knockdown , presenilin , zebrafish , microbiology and biotechnology , nicastrin , biology , apoptosis , notch signaling pathway , morpholino , signal transduction , alzheimer's disease , biochemistry , medicine , gene , disease
γ‐Secretase cleavage, mediated by a complex of presenilin, presenilin enhancer (Pen‐2), nicastrin, and Aph‐1, is the final proteolytic step in generating amyloid β protein found in brains of Alzheimer's disease patients and Notch intracellular domain critical for proper neuronal development. Here, we employ the zebrafish model to study the role of Pen‐2 in neuronal survival. We found that (i) knockdown of Pen‐2 using antisense morpholino led to a reduction of islet‐1 positive neurons, (ii) Notch signaling was reduced in embryos lacking Pen‐2 or other γ‐secretase components, (iii) neuronal loss in Pen‐2 knockdown embryos is not as a result of a lack of neuronal precursor cells or cell proliferation, (iv) absence of Pen‐2 caused massive apoptosis in the whole animal, which could be suppressed by simultaneous knockdown of the tumor suppressor p53, (v) loss of islet‐1 or acetylated tubulin positive neurons in Pen‐2 knockdown embryos could be partially rescued by knockdown of p53. Our results demonstrate that knockdown of Pen‐2 directly induces a p53‐dependent apoptotic pathway that contributes to neuronal loss and suggest that Pen‐2 plays an important role in promoting neuronal cell survival and protecting from apoptosis in vivo .