Modulation of BAG3 Expression and Proteasomal Activity by sAPPα Does Not Require Membrane-Tethered Holo-APP Arpita Kundu 1 & Nelli Milosch 1 & Patrick Antonietti 1 & Frederik Baumkötter 2 & Andreas Zymny 1 & Ulrike C. Müller 3 & Stefan Kins 2 & Parvana Hajieva 4 & Christian Behl 4 & Donat Kögel 1,5 Received: 22 July 2015 /Accepted: 19 October 2015 # Springer Science+Business Media New York 2015 Abstract Maintenance of intracellular proteostasis is essen- tial 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. Recent- ly, we provided evidence that membrane-bound holo-APP functionally cooperates with sAPPα to mediate neuroprotec- tion 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 ac- tivity in a dose-dependent manner in SH-SY5Y neuroblasto- ma 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 (sAPP β ) 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 phys- iological functions of APP and the interplay between APP processing and proteostasis during brain aging. Keywords Amyloid precursor protein . Alpha secretase . Autophagy . Proteasome Introduction The amyloid precursor protein (APP) has been implicated in a variety of physiological functions, including neuronal excit- ability, synaptogenesis/synaptic function, and neuronal sur- vival [1, 2]. Accumulating evidence support the concept that loss of these APP functions contributes to reduced neuronal plasticity, diminished synaptic signaling, and enhanced sus- ceptibility of neurons to cellular stress during brain aging [2]. Previous studies from our lab and other groups suggest that sAPPalpha (sAPPα) which is generated via cleavage of APP by the activity of α-secretase along the secretory pathway modulates the activity of stress and survival signaling path- ways to promote neuroprotection [2–5]. Recently, we could show that sAPPα is a key activator of the PI3K/Akt survival signaling pathway. Strikingly, we could also demonstrate that uncleaved holo-APP, but not APLP1 or APLP2, functionally * Donat Kögel koegel@em.uni-frankfurt.de 1 Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany 2 Division of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany 3 Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany 4 Institute of Pathobiochemistry, University Medical Center, Mainz University, Mainz, Germany 5 Experimental Neurosurgery, Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany Mol Neurobiol DOI 10.1007/s12035-015-9501-y