Elucidating the role of astrocytes in noradrenaline-mediated seizure suppression and its possible therapeutic relevance for Alzheimer's disease.

The prevalence of seizures in Alzheimer’s disease (AD) is high relative to age-matched controls. It is known that the amyloid beta (Aβ) peptide, central to AD pathology, is capable of inducing neuronal depolarization but is also released from neurons in an activity-dependent fashion. This indicates a potential positive feedback loop, accelerating disease progression. Noradrenergic signaling,  which is known to be anti-epileptic, is impaired early in AD. Interestingly, seizure-suppressing effects of noradrenaline (NA) have been correlated to increased GABA concentration. Astrocytes regulate extracellular levels of (neuro)transmitters, such as GABA, which controls excitability, and are key, if not primary, targets of NA signaling. I will then use the APP/PS1 mouse line to explore a possible link between NA signaling, astrocytes and seizure suppression in AD. I will first manipulate NA signaling in astrocytes and use electrophysiological and biochemical methods to measure seizure activity, (neuro)transmitter and Aβ levels ex vivo. I will then exploit the newly obtained knowledge to try and slow, or stop, the progression of Aβ buildup in vivo. The associated effects on cognitive function in APP/PS1 mice will be assayed using a battery of behavioral tests.
Establishing a central role for NA-triggered astrocyte activity in seizure suppression and Aβ accumulation would represent a paradigm shift, opening up new avenues for targeted therapeutics in AD.