APP-Mediated Signaling Prevents Memory Decline in Alzheimer’s Disease Mouse Model

Abstract

Summary: Amyloid precursor protein (APP) and its metabolites play key roles in Alzheimer’s disease (AD) pathophysiology. Whereas short amyloid-β (Aβ) peptides derived from APP are pathogenic, the APP holoprotein serves multiple purposes in the nervous system through its cell adhesion and receptor-like properties. Our studies focused on the signaling mediated by the APP cytoplasmic tail. We investigated whether sustained APP signaling during brain development might favor neuronal plasticity and memory process through a direct interaction with the heterotrimeric G-protein subunit GαS (stimulatory G-protein alpha subunit). Our results reveal that APP possesses autonomous regulatory capacity within its intracellular domain that promotes APP cell surface residence, precludes Aβ production, facilitates axodendritic development, and preserves cellular substrates of memory. Altogether, these events contribute to strengthening cognitive functions and are sufficient to modify the course of AD pathology. : Deyts et al. find that APP-mediated signaling, which occurs in lipid-raft microdomains through an interaction between APP C-tail and the heterotrimeric G-protein subunit GαS, provides a positive feedback regulatory loop that promotes non-amyloidogenic APP processing. Continuous GαS/cAMP-dependent signaling through APP C-tail preserves spatial memory in an Alzheimer’s disease mouse model. Keywords: amyloid precursor protein, APP processing, APP C-terminal fragment, Alzheimer disease mouse model, amyloidosis, G-protein signaling, adenylate cyclase, cognitive function, lipid raft