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

摘要

Amyloid precursor protein (APP) and its metabolitesplay key roles in Alzheimer’s disease (AD) pathophysiology.Whereas short amyloid-b (Ab) peptidesderived from APP are pathogenic, the APP holoproteinserves multiple purposes in the nervous systemthrough its cell adhesion and receptor-like properties.Our studies focused on the signaling mediated by theAPP cytoplasmic tail. We investigated whether sustainedAPP signaling during brain development mightfavor neuronal plasticity andmemory process througha direct interaction with the heterotrimeric G-proteinsubunit GaS (stimulatory G-protein alpha subunit).Our results reveal that APP possesses autonomousregulatory capacity within its intracellular domainthat promotes APP cell surface residence, precludesAb production, facilitates axodendritic development,and preserves cellular substrates of memory. Altogether,these events contribute to strengtheningcognitive functions and are sufficient to modify thecourse of AD pathology.