MRes Neuropharmacology, BSc Pharmacology
Investigating the molecular mechanisms behind the development of Alzheimer's Disease.
What came first, the chicken or the egg?
As an extension to the conventional amyloid-beta (Aβ) hypothesis, I am studying the role of epithelial sodium channel (ENaC) in upstream modulation of Aβ-regulated calcium influx in Alzheimer’s disease (AD). Whilst elevated Aβ monomers (Aβ0) are consistently observed upstream of events such as cell death or impaired capacity to undergo long term potentiation, directing resources towards preventing the formation of Aβ0 has not been successful in slowing the underlying disease progression in AD.
The role of ENaC in the CNS has been overlooked for several years, however my team has recently shown that blocking ENaC prevents enhancement of evoked calcium release, which is required for AD pathogenesis in-vivo. My teams recent discovery showed that ENaC functions in the brain as an effector of homeostatic presynaptic plasticity, where it is inserted into the presynaptic membrane during Aβ0-mediated presynaptic enhancement leading to the hypothesis that Aβ0 potentiates CaV2.1 voltage gated calcium channel function via a mechanism that is dependent upon activity of ENaC. CaV2.1 potentiation leads to an increase in the basal probability of neurotransmitter release that pathologically elevates synaptic activity, driving the loss of synaptic plasticity, cognitive deficits, and eventually spine loss - formulating the cognitive deficits observed in AD.
These findings will have a critical impact in the AD field, allowing the identification of new therapeutic targets therefore allowing us to intervene with disease progression.
I am also conducting work focussed on the role of peroxisomes in the development of AD pathophysiology. Peroxisomal degradation of fatty acids and production of reactive oxygen species (ROS) is tightly regulated in healthy cells, as the build up of ROS can cause DNA and protein damage. Peroxisomes are equipped for this by their ability to carry anti-oxidant enzymes that scavenge ROS. In aging cells, for various reasons, peroxisomes are not able to maintain a balance between ROS production and clearance. The damage caused by a build up of ROS can eventually lead to cell death. Not much is known about the role of peroxisomes in AD, however, could impaired peroxisomal function lead to accelerated aging of neurons and therefore contribute to the onset of AD? If so, is this a cause or consequence Aβ0 accumulation in AD?
Outside of my academic interests I like to Kayak, get involved with the digital arts and play a variety of console games.