Bibliographic
Glycogen synthase kinase-3β (GSK3β) is a highly conserved serine/threonine kinase that has highest abundance in the brain during development and is localized primarily in neurons. GSK3 is the major kinase which phosphorylates the microtubule binding protein tau and GSK3β has been shown to co-localize with neurofibrillary tangles in post-mortem AD brain. Abnormal hyperphosphorylation of tau leads to microtubule dysfunction and is believed to promote formation of paired helical filaments, a key component of neurofibrillary tangles Paired helical filaments are found in neuronal cell bodies and apical dendrites and are implicated as a causative agent in a number of neurodegenerative tauopathies. Consistent with this, over-expression of GSK3β in transgenic mice has been reported to cause tau hyperphosphorylation, neurodegeneration, and behavioral deficits. In addition, GSK3β has been implicated to have a role in synaptic plasticity in neuronal networks because of its influence on diverse substrates involved in signaling pathways. Inhibition of GSK3β facilitates induction of long-term potentiation (LTP) and blocks induction of long-term depression. Given the wide range of pathological and functional roles of GSK3β in the brain, it is important to identify a brain permeable small molecule GSK3 inhibitor that can be tested in the clinic for its therapeutic potential in the treatment of AD and related tauopathies.
In this study the authors report the discovery of AZD1080, a potent, selective, orally active, brain permeable GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies. AZD1080 inhibits tau phosphorylation in cells expressing human tau and in intact rat brain. In addition, subchronic but not acute administration with AZD1080 reverses MK-801-induced deficits, measured by long-term potentiation in hippocampal slices and in a cognitive test in mice, suggesting that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3β signaling. Based on the pre-clinical profile, AZD1080 may have both disease-modifying and symptomatic potential in the treatment of AD and related tauopathies.