sAPPalpha antagonizes dendritic degeneration and neuron death triggered by proteasomal stress.
Impaired proteasomal function is a major hallmark in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). Here we investigated the biological properties of the secreted cleavage product of APP (sAPPalpha) in antagonizing stress signalling, dendritic degeneration and neuronal cell death induced by the proteasome inhibitor epoxomicin. Analysis of executioner caspase activation demonstrated that sAPPalpha was able to protect PC12 cells from apoptosis triggered by epoxomicin, as well as by genotoxic stress (UV irradiation). This anti-apoptotic effect of sAPPalpha was associated with inhibition of the stress-triggered c-Jun N-terminal kinase (JNK)-signalling pathway. The anti-apoptotic effect of sAPPalpha could also be confirmed in organotypic slice cultures of Thy1-GFP mouse hippocampi. Confocal time-lapse imaging of CA1 pyramidal neurons revealed that preincubation with sAPPalpha preserves the structural integrity of neurons after epoxomicin treatment. Taken together, our data demonstrate that sAPPalpha is neuroprotective under conditions of proteasomal stress.
Copanaki
Ekaterini
E
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, D-60590 Frankfurt, Germany.
Chang
Steffi
S
Vlachos
Andreas
A
Tschäpe
Jakob-A
JA
Müller
Ulrike C
UC
Kögel
Donat
D
Deller
Thomas
T
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000737:chemistry; D046508:Culture Techniques; D049229:Dendritic Spines / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D009410:Nerve Degeneration; D009842:Oligopeptides / Q000494:pharmacology; D016716:PC12 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins; D018800:Thy-1 Antigens; D014466:Ultraviolet Rays
D016564:Amyloid beta-Protein Precursor; D002867:Chromones; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D009025:Morpholines; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D018800:Thy-1 Antigens; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048031:JNK Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin