Modulation of BAG3 Expression and Proteasomal Activity by sAPPα Does Not Require Membrane-Tethered Holo-APP

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 (sAPP alpha), 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 sAPP alpha to mediate neuroprotection via activation of the Akt survival signaling pathway and sAPP alpha directly affects proteostasis. Here, we demonstrate that in addition to its anti-apoptotic function, sAPP alpha has effects on neuronal proteostasis under conditions of proteasomal stress. In particular, recombinant sAPP alpha 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, sAPP alpha was able to inhibit MG132-induced BAG3 expression in primary hippocampal neurons. Strikingly, these sAPP alpha-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 sAPP alpha. Importantly, recombinant sAPPbeta (sAPP beta) failed to modulate BAG3 expression and proteostasis in APP-proficient wild-type (wt) cells, indicating that these biological effects are highly selective for sAPP alpha. In conclusion, we demonstrate that modulation of proteostasis is a distinct biological function of sAPP alpha 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.