Characterising novel drug mechanisms in Alzheimer’s disease

Alzheimer’s disease (AD) is, arguably, caused by the accumulation, in the brain, of neurotoxic amyloid beta (Abeta)-peptides derived from the larger amyloid precursor protein (APP) through the action of beta- and gamma-secretase enzymes. This ’amyloidogenic’ pathway of APP proteolysis exhibits a reciprocal relationship with the ’non-amyloidogenic’ pathway in which the protein is cleaved by an alpha-secretase activity within the Abeta domain thereby precluding intact neurotoxic peptide formation. This latter pathway is also beneficial in that it yields a large soluble fragment called soluble APPalpha (sAPPalpha) which is neuroprotective.

We have recently identified a drug which stimulates the non-amyloidogenic pathway of APP proteolysis enhancing the production of neuroprotective sAPPalpha and dramatically reducing the formation of Abeta-peptides. Our data are extremely exciting given that the drug is already used to treat an unrelated condition and traverses the blood-brain-barrier.

We now wish to determine the mechanisms by which the drug regulates APP proteolysis. The successful applicant would examine the effects of the drug on the subcellular distribution of APP and its secretases using fluorescence-labelled constructs expressed in neuronal cell cultures and examine its effects on the expression levels, maturation and activity of the secretases responsible for APP processing. In addition, they would investigate the effects of combining our new drug with GLP-1 mimetics such as liraglutide and endexin-4 on cell proliferation and APP processing. The project will provide an excellent opportunity to gain experience in mammalian cell culture, molecular biology, fluorescence microscopy, proliferation assays, gel electrophoresis and Western blotting.

Applications are made by complete an application for PhD Biomedical and Life Sciences October 2017 through our online application system. Closing date, midnight 3rd April 2017. Informal enquires about the project should be made directly to Dr Ed Parkin.