Abstract
Dysregulation of neuronal zinc homeostasis plays a major role in many processes related to brain aging and neurodegenerative diseases, including Alzheimer's disease (AD). Yet, despite the critical role of zinc in neuronal function, the cellular mechanisms underpinning its homeostatic control are far from clear. We reported that the cellular prion protein (PrP(C)) is involved in the uptake of zinc into neurons. This PrP(C)-mediated zinc influx required the metal-binding octapeptide repeats in PrP(C) and the presence of the zinc permeable AMPA channel with which PrP(C) directly interacted. Together with the observation that PrP(C) is evolutionarily related to the ZIP family of zinc transporters, these studies indicate that PrP(C) plays a key role in neuronal zinc homeostasis. Therefore, PrP(C) could contribute to cognitive health and protect against age-related zinc dyshomeostasis but PrP(C) has also been identified as a receptor for amyloid-β oligomers which accumulate in the brains of those with AD. We propose that the different roles that PrP(C) has are due to its interaction with different ligands and/or co-receptors in lipid raft-based signaling/transport complexes.