Dissecting the copper bioinorganic chemistry of the functional and pathological roles of the prion protein: Relevance in Alzheimer's disease and cancer

A pathological hallmark of Alzheimer’s disease (AD) is an accumulation of insoluble plaque containing the amyloid-β peptide (Aβ) of 40–42 aa residues1. Prefibrillar, soluble oligomers of Aβ have been recognized to be early and key intermediates in AD-related synaptic dysfunction2–9. At nanomolar concentrations, soluble Aβ-oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5,8 and impair rodent spatial memory2. Soluble Aβ-oligomers have been prepared from chemical syntheses, from transfected cell culture supernatants, from transgenic mouse brain and from human AD brain2,4,7,9. 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 (PrPC) as an Aβ-oligomer receptor by expression cloning. Aβ-oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc 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 PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric β. Thus, PrPC is a mediator of Aβoligomer induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease. Show more

In spite of advances in understanding the role of the cellular prion protein (PrP) in neural cell interactions, the mechanisms of PrP function remain poorly characterized. We show that PrP interacts directly with the neural cell adhesion molecule (NCAM) and associates with NCAM at the neuronal cell surface. Both cis and trans interactions between NCAM at the neuronal surface and PrP promote recruitment of NCAM to lipid rafts and thereby regulate activation of fyn kinase, an enzyme involved in NCAM-mediated signaling. Cis and trans interactions between NCAM and PrP promote neurite outgrowth. When these interactions are disrupted in NCAM-deficient and PrP-deficient neurons or by PrP antibodies, NCAM/PrP-dependent neurite outgrowth is arrested, indicating that PrP is involved in nervous system development cooperating with NCAM as a signaling receptor. Show more