The molecular mechanisms linking amyloid-beta, the prion protein and tau in Alzheimer's disease

Autor: Noble, Elizabeth
Rok vydání: 2017
Předmět:
Druh dokumentu: Electronic Thesis or Dissertation
Popis: Several lines of evidence suggest that the expression of the cellular prion protein (PrPC) is altered with age and in sporadic Alzheimer’s disease, however, published results have been contradictory. Furthermore, a relationship between the expression of PrPC and Tau has started to emerge. We have revealed a specific relationship between the expression of PrPC and Tau in neuroblastoma cell lines and transgenic mouse models. In addition, we identified that the expression levels of PrPC are reduced in multiple brain regions following the progression of sporadic Alzheimer’s disease. Furthermore, the reduction in PrPC expression significantly correlated with the reduction in Tau expression and coincided with an increase in Tau pathology. In addition, data from neuroblastoma cell lines implicated the glycosylphosphatidylinositol (GPI)-anchor and in part the localisation of PrPC to lipid rafts in mediating these alterations to Tau. We hypothesise that the reduction in PrPC expression reflects a primary mechanism in Alzheimer’s disease pathogenesis and indirectly triggers the reduction in Tau expression which subsequently contributes to neuronal destabilisation and disruption to neuronal function. Soluble oligomeric forms of amyloid-beta are the primary pathogenic species in Alzheimer’s disease and strongly correlate with the presence and severity of cognitive decline. PrPC acts as a high affinity neuronal receptor for amyloid-beta oligomers and triggers pathogenic signaling cascades which induce synaptic impairment and further exacerbate neuronal destabilisation. We demonstrated that Flotillin-1 and the lipid raft localisation of PrPC are essential for the binding of amyloid-beta oligomers to PrPC. Furthermore, the metabotropic glutamate receptor, mGluR5 plays a pivotal role in the aberrant signaling of PrPC, and this PrPC/mGluR5 complex provides a mechanistic link between extracellular amyloid-beta oligomers and intracellular Tau phosphorylation, by Fyn kinase, Pyk2 and possibly by inactivation of the protein phosphatase, PP2A. Considering there is now strong evidence that Tau is the mediator of amyloid-beta induced toxicity, the reduction in Tau levels mediated by PrPC may be a protective mechanism. amyloid-beta oligomers interact with a multitude of neuronal receptors in addition to PrPC. It is likely that activation of multiple receptor complexes and signalling cascades are responsible for synaptic impairment and Tau phosphorylation induced by amyloid-beta, however, these complexes remain to be fully determined. Investigating amyloid-beta oligomer induced Tau phosphorylation in vitro has proven challenging, however, we suggest that a functional, mature, neuronal model is necessary to induce the complex mechanisms linking extracellular amyloid-beta oligomers and the phosphorylation of intracellular Tau. A greater understanding of the complex relationship between amyloid-beta, PrPC and Tau will aid in our understanding of the molecular mechanisms underlying Alzheimer’s disease and in the discovery of novel therapeutic targets for this progressive neurodegenerative disease.
Databáze: Networked Digital Library of Theses & Dissertations
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