Abstract
Alzheimer’s disease (AD) is the most common form of dementia with the characteristic symptom of progressive memory impairment. This is thought to be underpinned by the primary pathological features of neuronal and synaptic loss. The Group I p21-activated kinases (PAKs) are involved in regulating neuronal structure, which is crucial for the generation and maintenance of neuronal connections and functional signal transmission. Interestingly, evidence suggests that PAK levels are reduced in the brains of AD patients. The potential consequences of this for neuronal function will largely depend upon the roles PAKs play in neuronal physiology, the understanding of which is still being developed.Synaptic plasticity is widely considered to underlie the cellular mechanisms of memory, and so has been the focus of extensive study in trying to understand the causes of cognitive impairment in AD. We studied the role of PAKs in the long-term potentiation (LTP) form of synaptic plasticity in acute hippocampal rat slices. We found that treatment of slices with IPA-3, a pharmacological PAK inhibitor, blocks LTP. However, another PAK inhibitor - FRAX486 - does not. As PAKs regulate cellular morphology, we stimulated synapse growth in cultured hippocampal neurons and examined the size of dendritic spines in the presence and absence of the PAK inhibitors. Consistent with our electrophysiology data, we found that IPA-3-treated neurons showed marked reductions in size, and FRAX486-treated neurons and controls did not. These observations suggest that IPA-3 and FRAX486 act differently on PAK function and that PAKs may have an influence on steps in the signalling cascade that triggers LTP. Further characterisation of the physiological roles PAK proteins play in neuronal function will be important to understand the possible consequence of their decline in AD.
| Date of Award | 23 Mar 2021 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | CONACyT |
| Supervisor | Daniel Whitcomb (Supervisor) & Gavin I Welsh (Supervisor) |