AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by cognitive impairment. Amyloid-β (Aβ), a peptide generated from the cleavage of amyloid precursor protein (APP), is a pathological hallmark of AD and believed to underlie the synaptic pathophysiology of the disease. Synaptic malformations are accompanied by electrophysiological phenotypes, including the inhibition of long term potentiation (LTP) and facilitation of long term depression (LTD). Furthermore, Aβ can disrupt α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) trafficking, a key determinant of synaptic strength and synaptic plasticity, by causing their removal from the synaptic surface. Based on the observation that GluA1 and GluA2 protein levels are reduced in AD post-mortem brains, this synaptic removal could be a result of degradation of these subunits.
A multitude of proteins interact with AMPARs to control their trafficking including cortactin, which maintains surface levels of GluA2-containing AMPARs by directing receptors away from lysosomes. This interaction is negatively regulated by Src family kinase (SFK) phosphorylation of cortactin. Since the SFK family demonstrates aberrant activity in response to Aβ, disruption of the cortactin-GluA2 interaction might be responsible for AMPAR trafficking abnormalities in the disease.
Here we show that the GluA2 but not GluA1 receptor subunit displays reduced expression in two models of amyloidopathy. Furthermore, overexpressing APPWT in hippocampal neuronal cultures causes the targeting of GluA2-containing AMPARs to lysosomal compartments. An increase in the phosphorylation of the Y466 cortactin residue was also demonstrated in response to APPSWE expression.
The results suggest that Aβ disrupts the trafficking of GluA2-containing AMPARs by directing receptors for lysosomal degradation. This could be a result of increased cortactin phosphorylation which disrupts the GluA2-cortactin interaction so that receptors cannot be directed away from lysosomes.
|Date of Award||29 Sep 2020|
|Supervisor||Pete J Cullen (Supervisor) & Jonathan G Hanley (Supervisor)|
- Alzheimer's disease
- Receptor trafficking