Investigating the role of Kv3.4 potassium channels in neurodegenerative pathways of relevance to Alzheimer's Disease.

Alzheimer's disease (AD) accounts for almost 2/3 of the cases of dementia, and affects approxiamately 1% of the world's population. Currently four out of the five pharmacological treatments used for AD are acetylcholinesterase inhibitors aimed at boosting the amount of acetylcholine in the brain, with the fifth being an N-methyl-D-aspartate (NMDA) receptor antagonist. These treatments are purely symptomatic and it is clear they have no significant effect on the prevention or delay of disease progression. Due to the lack of effective pharmaceutical intervention and the debilitating nature of the disease, there is an increasing cost to society in the form of psychosocial therapy and care giving. It is estimated that in the UK alone, AD costs the economy £23 billion a year (ARUK, 2012) and with an aging population, this figure is only going to increase without effective management or prevention.

The Amyloid Cascade hypothesis suggests that in both familial and sporadic AD, amyloid beta (AB peptide) accumulation in the brain is the primary culprit in driving AD pathology. This hypothesis has driven drug development for AD for decades with no real translation to a beneficial treatment for patients (Karran & Hardy, 2014, Ann Neurol; 76(2):185-205). Due to a number of recent large Phase II/III failures based around the Amyloid Cascade hypothesis there is an increasing effort to identify novel therapeutic strategies for treating AD. Recently, the voltage gated potassium channel Kv3.4 subunit, which underlies the fast-inactivating K+ currents (IA), has been recognized to be relevant for AD pathogenesis and is emerging as a new target candidate for AD.

Accumulating evidence suggests that Kv3.4, like Kv3.3, may also play a role in cell fate. Kv3.4 protein was found to be overexpressed in post-mortem brain from patients in the early stages of AD; in more advanced stages, Kv3.4 was present at high levels in degenerated structures. A similar up-regulation of Kv3.4 was also observed in the Tg2576 transgenic mouse model of AD which carries a human APP gene mutation (Angulo et al., 2004, J Neurochem; 91(3):547-57). More recently Kv3.4 channels were reported to be up-regulated in astrocytes exposed to AB oligomers and in astrocytes of Tg2576 mice (Boscia et al., 2017, Neurobiology of Aging; doi: 10.1016/j.neurobiolaging.2017.03.008).

In the current project we will utilise inflammatory in vitro assays, preclinical in vivo models and human post-mortem tissue to investigate the role of Kv3.4 in neurodegenerative pathways of relevance to AD with the goal to provide a platform for testing novel drugs targeting this receptor.