Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen‐2) demonstrate excessive p53‐dependent apoptosis and neuronal loss

• Published in: Journal of neurochemistry 2006-03, Vol.96 (5), p.1423-1440
• Main Authors: Campbell, William A., Yang, Hongwei, Zetterberg, Henrik, Baulac, Stéphanie, Sears, Jacqueline A., Liu, Tianming, Wong, Stephen T. C., Zhong, Tao P., Xia, Weiming
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Alzheimer Disease; Alzheimer's disease; Animal; Animals; Animals, Genetically Modified; Antisense; Apoptosis; Apoptosis - genetics; Biological and medical sciences; Blotting; Blotting, Northern; Blotting, Western - methods; Body Patterning; Body Patterning - drug effects; Body Patterning - genetics; Cell Count; Cell Count - methods; Cell physiology; chemistry; Danio rerio; deficiency; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Developmental; diagnostic use; Disease Models; Disease Models, Animal; Dose-Response Relationship; Dose-Response Relationship, Drug; Drug; drug effects; Embryo; Embryo, Nonmammalian; Fish; Fish Proteins; Fish Proteins - chemistry; Fish Proteins - deficiency; Fish Proteins - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Genetically Modified; genetics; Immunohistochemistry; Immunohistochemistry - methods; In Situ Hybridization; In Situ Hybridization - methods; In Situ Nick-End Labeling; In Situ Nick-End Labeling - methods; Indoles; Medical sciences; Membrane Proteins; Membrane Proteins - chemistry; Membrane Proteins - deficiency; Membrane Proteins - metabolism; Membrane Proteins - physiology; Messenger; metabolism; methods; Molecular and cellular biology; Neurology; Neurons; Neurons - metabolism; Nonmammalian; Northern; Notch; Oligonucleotides; Oligonucleotides, Antisense - pharmacology; Pen‐2; pharmacology; physiology; presenilin; Presenilin-2; Proteins; Psychiatry; Psykiatri; Receptors; Receptors, Notch - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA; RNA, Messenger - metabolism; Tumor Suppressor Protein p53; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism; Western; Zebrafish; Zebrafish Proteins; Zebrafish Proteins - deficiency; Zebrafish Proteins - metabolism; γ‐secretase
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03648.x

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.