Journal of Alzheimers Disease & Parkinsonism
Open Access

Abstract

The cellular prion protein (PrPC) is ahigh-affinity neuronal receptorfor amyloid-β (Aβ) oligomers, mediating neuronal impairment via the activation of Fyn kinase and phosphorylation of tau. The β-secretase, ADAM10, which cleaves the amyloid precursor protein (APP) releasing the neuroprotectives APPβ and precluding the formation of Aβ, also sheds PrPC from the cell surface. It is hypothesised that modulation of the shedding of PrPC by ADAM10 would alter the binding and neurotoxicity of Aβ oligomers. SH-SY5Y cells were treated with siRNA targeted against ADAM10 or with pharmacological agents (e.g. carbachol, resveratrol) to reduce or activate ADAM10 activity, respectively. siRNA knockdown of ADAM10 resulted in increased full length PrPC at the cell surface and increased the amount of Aβ oligomers bound to the cells. Antibody blocking of the Aβoligomer binding site on PrPC prevented the increase in binding observed following ADAM10 siRNA. Conversely, up-regulation of ADAM10 activity promoted the shedding of PrPC from the cell surface, and consequently reduced the binding of Aβ oligomers to cells. The specificity of each activator for ADAM10 was tested by monitoring sAPPα production following siRNA knockdown of ADAM10. Carbachol modulates ADAM10 activity, but also modulates sAPPα production via a different pathway, whereas resveratrol solely modulates sAPPα production via ADAM10. Developing specific agonists of ADAM10 will not only preclude Aβ formation and up-regulate neuroprotectives APPα, but it will also prevent the binding of soluble Aβ oligomers to PrPC and prevent the aberrant activation of signaling pathways which lead to neurotoxicity.

Biography

Heledd H Griffiths has been researching into the cell biology of Alzheimer�s disease for 9 years with Professor Nigel Hooper. She gained her PhD from the University of Leeds at the age of 27, in 2009. As a post-doctoral researcher, she has been awarded two 3-year funded grants from Alzheimer�s Research, UK. Work from her first grant was published in the Journal of Biological Chemistry and awarded �Best paper in neurobiology 2013�. She has recently moved over to the University of Manchester alongside Professor Nigel Hooper to continue her research. She has published 9 papers and currently has 3 under review.