Despite Alzheimer’s disease (AD) being the most common form of dementia, our understanding of the molecular mechanisms that underlie the severe cognitive impairments of AD patients remains very incomplete. A well-supported hypothesis is that AD pathology disrupts neuronal communication at the synapse, a process thought to be crucial for memory function. Amyloid beta (Aβ) and phosphorylated tau (P-Tau) are key molecules in driving the impairment of synaptic function, but the molecular mechanisms involved in their neurotoxic effects are not fully characterised. Compelling evidence has positioned two types of synaptic G-protein coupled receptor (GPCRs), muscarinic acetylcholine receptors (mAChRs) and metabotropic glutamate receptors (mGluRs), as emerging mediators of such effects. They are both coupled to the same intracellular pathways but still appear to play differential roles in pathological mechanisms. Research has shown that blockade of mGluRs and upregulation of mAChRs are beneficial for synaptic function in in vitro and in vivo models of AD. The aim of this study is first to investigate the consequences of mGluRs activation in physiological conditions, to assess whether it is sufficient to cause synaptic impairments and whether it can regulate mAChRs function. Second, to characterise the expression of these synaptic GPCRs in the pathology of AD, to evaluate whether their potential interplay may be relevant to disease mechanisms. Third, to investigate the effects of P-tau, a key mediator of AD pathology, on the function of these synaptic GPCRs. Results from this study showed a functional interplay between mGluRs and mAChRs and a differential regulation of both their protein levels in AD brains and their function in the presence of P-tau. Altogether, this work provides new insights into possible mechanisms that contribute to synaptic dysfunction in AD, which will help to design therapeutic strategies to combat this devastating disorder.
|Date of Award||23 Jan 2019|
- The University of Bristol
|Supervisor||Daniel Whitcomb (Supervisor) & Shelley Allen-Birt (Supervisor)|