title: Modulation of BAG3 Expression and Proteasomal Activity by sAPPα Does Not Require Membrane-Tethered Holo-APP.
abstract: Maintenance of intracellular proteostasis is essential for neuronal function, and emerging data support the view that disturbed proteostasis plays an important role in brain aging and the pathogenesis of age-related neurodegenerative disorders such as Alzheimer's disease (AD). sAPPalpha (sAPPα), the extracellularly secreted N-terminal alpha secretase cleavage product of the amyloid precursor protein (APP), has an established function in neuroprotection. Recently, we provided evidence that membrane-bound holo-APP functionally cooperates with sAPPα to mediate neuroprotection via activation of the Akt survival signaling pathway and sAPPα directly affects proteostasis. Here, we demonstrate that in addition to its anti-apoptotic function, sAPPα has effects on neuronal proteostasis under conditions of proteasomal stress. In particular, recombinant sAPPα significantly suppressed MG132-triggered expression of the co-chaperone BAG3 and aggresome formation, and it partially rescued proteasomal activity in a dose-dependent manner in SH-SY5Y neuroblastoma cells. In analogy, sAPPα was able to inhibit MG132-induced BAG3 expression in primary hippocampal neurons. Strikingly, these sAPPα-induced changes were unaltered in APP-depleted SH-SY5Y cells and APP-deficient neurons, demonstrating that holo-APP is not required for this particular function of sAPPα. Importantly, recombinant sAPPbeta (sAPPβ) failed to modulate BAG3 expression and proteostasis in APP-proficient wild-type (wt) cells, indicating that these biological effects are highly selective for sAPPα. In conclusion, we demonstrate that modulation of proteostasis is a distinct biological function of sAPPα and does not require surface-bound holo-APP. Our data shed new light on the physiological functions of APP and the interplay between APP processing and proteostasis during brain aging.
authors.affiliation: Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany.
authors.forename: Arpita
authors.initials: A
authors.lastname: Kundu
authors.affiliation: Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany.
authors.forename: Nelli
authors.initials: N
authors.lastname: Milosch
authors.affiliation: Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Antonietti
authors.affiliation: Division of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Baumkötter
authors.affiliation: Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zymny
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
authors.forename: Ulrike C
authors.initials: UC
authors.lastname: Müller
authors.affiliation: Division of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kins
authors.affiliation: Institute of Pathobiochemistry, University Medical Center, Mainz University, Mainz, Germany.
authors.forename: Parvana
authors.initials: P
authors.lastname: Hajieva
authors.affiliation: Institute of Pathobiochemistry, University Medical Center, Mainz University, Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
authors.affiliation: Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany. koegel@em.uni-frankfurt.de.|Experimental Neurosurgery, Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany. koegel@em.uni-frankfurt.de.
authors.forename: Donat
authors.initials: D
authors.lastname: Kögel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D007976:Leupeptins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Alpha secretase; Amyloid precursor protein; Autophagy; Proteasome