Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers

Abstract

A pathological hallmark of Alzheimer’s disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40–42 aa residues 1. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction 2– 9. At nanomolar concentrations, soluble Aβ-oligomers block hippocampal long-term potentiation 7, cause dendritic spine retraction from pyramidal cells 5, 8 and impair rodent spatial memory 2. Soluble Aβ-oligomers have been prepared from chemical syntheses, from transfected cell culture supernatants, from transgenic mouse brain and from human AD brain 2, 4, 7, 9. Together, these data imply a high affinity cell surface receptor for soluble Aβ-oligomers on neurons, one that is central to the pathophysiological process in AD. Here, we identify the cellular Prion Protein (PrP ^C) as an Aβ-oligomer receptor by expression cloning. Aβ-oligomers bind with nanomolar affinity to PrP ^C, but the interaction does not require the infectious PrP ^Sc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the Aβ-oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent Aβ-oligomer binding to PrP ^C and rescue synaptic plasticity in hippocampal slices from oligomeric β. Thus, PrP ^C is a mediator of Aβoligomer induced synaptic dysfunction, and PrP ^C-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.