... understanding life in molecular detail

Prof Nigel Hooper

Alzheimer’s, amyloid, prion, lipid rafts

Alzheimer’s disease is characterised by the accumulation in the brain of amyloid-ß (Aß) peptides. We are investigating the molecular and cellular regulation of Aß production and action, particularly the interaction of Aß oligomers with the prion protein within cholesterol-rich lipid rafts. Other work in the group includes investigation into neuronal zinc metabolism, the link between diabetes and Alzheimer’s disease and the posttranslational processing of the low density lipoprotein receptor.

Current major projects include:
  • Mechanism of action of amyloid-Ã? oligomers in Alzheimerâ??s disease.
  • Molecular and cellular regulation of amyloid-Ã? production
  • Neuronal zinc metabolism in neurodegeneration and ageing.
  • Proteolytic processing of cell surface receptors.

Prion protein in zinc metabolism and action of amyloid-β oligomers in Alzheimer’s disease

Nigel Hooper, Rob Andrew, Heledd Griffiths, Kate Kellett, Nicole Watt, Isobel Whitehouse


Alzheimer’s disease (AD) is the commonest neurodegenerative disease of old age. Currently, there are no drugs available to halt or slow the progression of this devastating disease which is placing a huge burden on patients and carers. AD is characterised by the deposition in the brain of senile plaques that are composed of the amyloid-β peptide (Aβ). Through mechanisms that are poorly understood, Aβ oligomers, fibrils and/or aggregates are toxic to nerve cells.

The prion protein is probably best known for its role in the transmissible spongiform encephalopathies or prion diseases, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cattle. In these diseases the normal cellular form of the prion protein (PrPC) undergoes a conformational conversion to the infectious form, PrPSc. However, understanding the physiological role(s) of PrPC and whether loss of these contribute to disease are critical.

Regulation of Aβ toxicity by the prion protein

Fig. 1. Binding of Aβ oligomers (AβO) to rat primary hippocampal neurons expressing PrPC (PrP).

PrPC was recently identified as a high-affinity neuronal receptor for Aβ oligomers. We report that fibrillar Aβ oligomers recognised by the OC antibody, which have been shown to correlate with the onset and severity of AD, bind preferentially to cells and neurons expressing PrPC (Fig. 1). The binding of Aβ oligomers to cell surface PrPC, as well as their downstream activation of Fyn kinase, was dependent on the integrity of cholesterol-rich lipid rafts. Fluorescence microscopy and co-localisation with sub-cellular markers revealed that the Aβ oligomers co-internalised with PrPC, accumulated in endosomes and subsequently trafficked to lysosomes. The cell surface binding, internalisation and downstream toxicity of Ab oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of Aβ oligomers to cell surface PrPC impaired its ability to inhibit the activity of the β-secretase BACE1 which cleaves the amyloid precursor protein to produce Aβ. The green tea polyphenol (-)-epigallocatechin gallate (EGCG) and the red wine extract resveratrol both re-modelled the fibrillar conformation of Aβ oligomers. The resulting non-fibrillar oligomers displayed significantly reduced binding to PrPC-expressing cells and were no longer cytotoxic. These data indicate that soluble, fibrillar Aβ 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 Aβ oligomers in AD.

The prion protein facilitates zinc uptake into neurons

Fig. 2. Schematic for how PrPC mediates zinc uptake into cells through AMPA receptors and affects intracellular tyrosine kinase activity.

Zinc is released into the synaptic cleft upon exocytotic stimuli, although the mechanism for its reuptake into neurons is unresolved. Using zinc specific fluorescent dyes we reported that PrPC enhances the uptake of zinc into neuronal cells. This PrPC-mediated zinc influx required the octapeptide repeats and N-terminal polybasic region in PrPC but not its endocytosis. Selective antagonists of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors blocked the PrPC-mediated zinc uptake and PrPC co-immunoprecipitated with both GluA1 and GluA2 AMPA receptor subunits. Zinc-sensitive intracellular tyrosine phosphatase activity was decreased in cells expressing PrPC and increased in the brains of PrPC null mice, providing evidence of a physiological consequence of the process (Fig. 2). This PrPC-mediated zinc uptake was ablated in cells expressing familial prion disease-associated mutants of PrPC and in prion-infected cells. These data suggest that alterations in PrPC-mediated zinc uptake may contribute to neurodegeneration in prion and other neurodegenerative diseases.

Detailed research programme                  Close ▲

Selected Publications

  1. Watt, N. T., Taylor, D. R., Kerrigan, T. L., Griffiths, H. H., Rushworth, J. V., Whitehouse, I. J. & Hooper, N. M. (2012) Prion protein facilitates uptake of zinc into neuronal cells. Nature Communications 3, doi:10.1038/ncomms2135.

  2. Rushworth, J. V., Griffiths, H. H., Watt, N. T. & Hooper, N.M. (2013) Prion protein-mediated neurotoxicity of amyloid-ß oligomers requires lipid rafts and the transmembrane LRP1. J. Biol. Chem. 288, 8935-8951.

  3. Griffiths, H. H., Whitehouse, I. J., Baybutt, H., Brown, D., Kellett, K. A. B., Jackson, C. D., Turner, A. J., Piccardo, P., Manson, J. C. and Hooper, N. M. (2011) Prion protein interacts with BACE1 protein and differentially regulates its activity toward wild type and swedish mutant amyloid precursor protein. J. Biol. Chem. 286, 33489-33500.

  4. Whitehouse, I. J., Miners, J.S., Glennon, E.B.C., Kehoe, P.G., Love, S., Kellett, K.A.B. and Hooper, N.M. (2013) Prion protein is decreased in Alzheimer’s brain and inversely correlates with BACE1 activity, amyloid-ß levels and Braak stage. PLoS ONE 8(4): e59554