Alzheimer’s disease (AD) results in severe age-related cognitive decline and neurodegeneration. Prior to gross neurodegeneration, at a stage where disease-modifying therapeutic intervention is likely to be beneficial, AD is associated with substantial deficits in synaptic function and the structure of dendritic spines, which house synapses.
MicroRNAs (miRNAs) are small noncoding endogenous RNAs that repress translation of target mRNAs by associating with Argonaute (Ago) proteins, underpinning a powerful mechanism for fine-tuning protein expression. Specific miRNAs are known to modulate the translation of proteins involved in spine morphogenesis or synaptic plasticity. While miRNAs are implicated in AD, mechanisms for the dysfunctional regulation of Ago2 and the miRNA machinery in the early stages of AD are unknown.
We have shown that activity-dependent dendritic spine shrinkage requires an increase in miRNA activity caused by Ago2 phosphorylation, and consequent increases in specific Ago2 protein interactions (paper submitted). This leads to the hypothesis that chronic up-regulation of miRNA activity via Ago2 phosphorylation is a critical mechanism involved in the loss of spines and synaptic dysfunction in AD.
The project will test our hypothesis via 2 main approaches: 1) Genetic manipulation of mouse models of AD by viral vectors to replace endogenous Ago2 with mutants to block phosphorylation. Synaptic function will be analysed by electrophysiology in hippocampal slices, and dendritic spine morphology will be studied using histological techniques or 2-photon imaging. 2) Application of β-amyloid (Aβ) oligomers to cultured neurons expressing Ago2 mutants. This will define which miRNAs are affected via this mechanism, how synaptic protein expression is affected, and details of the signalling pathways leading to Aβ-induced Ago2 phosphoregulation.
Our hypotheses predict that blocking Ago2 phosphorylation will reduce miRNA dysfunction, dendritic spine loss and synaptic deficits associated with AD. Hence, we anticipate that the project will define these molecular pathways as therapeutic targets.
We are looking for an enthusiastic and innovative student with an excellent degree in neuroscience, biological or medical science. The successful candidate will be based at the University of Bristol Faculty of Biomedical Sciences, with some of the project carried out in the University of Exeter Medical School. The project will be carried out under the expert supervision of Dr. Jonathan Hanley (neuronal cell biology and biochemistry, Bristol), Dr. Jon Brown (slice electrophysiology, Exeter) and Dr. Mike Ashby (2-photon imaging, Bristol). For further information on this project please contact Jonathan Hanley ([email protected]).