Cellular Prion Protein as a Therapeutic Target in Alzheimer's Disease

Abstract

Soluble oligomeric species of amyloid-β (Aβ) peptide are presumed to be drivers of synaptic impairment, and the resulting cognitive dysfunction in Alzheimer's disease. In 2009, cellular prion protein (PrP^C) was identified in a genome-wide screen as a high-affinity receptor for Aβ oligomers, and since then, many studies have explored the role of PrP^C in Alzheimer's disease. Herein, I systematically assess the current level of target validation for PrP^C in Alzheimer's disease and the merits of the identified approaches to therapeutically affect the PrP^C:Aβ oligomer-interaction. The interaction of Aβ oligomers with PrP^C in mice impairs hippocampal long-term potentiation, memory, and learning in a manner that involves Fyn, tau, and glutamate receptors. Furthermore, PrP^C acts to catalyze the formation of certain Aβ oligomeric species in the synapse and may mediate the toxic effects of other β-sheet rich oligomers as well. Therapeutic approaches utilizing soluble PrP^C ectodomain or monoclonal antibodies targeting PrP^C can at least partially prevent the neurotoxic effects of Aβ oligomers in mice.