Prion Protein As A Therapeutic Target In Alzheimer?s Disease | 21896
Journal of Alzheimers Disease & Parkinsonism
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Soluble oligomeric forms of amyloid-? (A?) appear to be the most neurotoxic assemblies in Alzheimer?s disease (AD). The
cellular prion protein (PrPC) is a neuronal surface receptor for soluble A? oligomers, mediating their neurotoxicity. A
cholesterol-rich, lipid raft-based cell surface complex, along with the transmembrane low density lipoprotein receptor-related
protein-1 (LRP1), is critical for mediating the neurotoxic effects of A? oligomers, including the activation of Fyn kinase.
Remodelling of the A? oligomers with the polyphenols resveratrol or EGCG prevents their binding to PrPC and the downstream
neuronal toxicity. These data indicate that soluble A? oligomers bind to PrPC in a conformation-dependent manner and require
the integrity of lipid rafts and the transmembrane LRP1 for their cytotoxicity, thus revealing potential targets to alleviate the
neurotoxic properties of A? oligomers in AD. However, PrPC is also involved in regulating the production of A? through its
inhibition of the ?-secretase BACE1 and enhances the uptake of zinc into neurons through AMPA receptors. A reduction in
PrPC results in an increase in A? and in synaptic zinc which promotes the formation of A? oligomers. In the human brain in
AD and aging there is a reduction in PrPC, which inversely correlates with BACE1 activity and A? levels, consistent with its
role as a neuroprotective agent. This apparent dichotomy in the role of PrPC in AD (neurotoxic versus neuroprotective) will be
discussed, along with the potential for, and limitations with, PrPC being a therapeutic target in AD.
Nigel M Hooper completed his PhD at the University of Leeds in 1987. He was then awarded a Mr and Mrs John Jaffe Donation Research Fellowship from the
Royal Society. Between 1989 and 2014, he was on the academic staff, including as Professor of Biochemistry, and Dean of the Faculty of Biological Sciences, at
the University of Leeds. He has recently taken up a Chair appointment in the Institute of Brain, Behaviour and Mental Health at the University of Manchester. He is
Chair of the Scientific Advisory Board of Alzheimer?s Research UK and has published over 170 research papers.
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