Identification of ferroptosis dependent Tau kinase activity in two in vitro models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder resulting from aggregation of the Tau protein and amyloid-β (Aβ) plaques in the brain. Iron dysbiosis appears to be the common theme prevalent across neurodegenerative diseases by promoting aggregation and pathogenicity of the characteristic aberrant proteins, β-amyloid, Tau, α-synuclein, and TDP43, in these diseases. Studies have demonstrated that iron can regulate Tau phosphorylation by inducing the activity of multiple kinases. The involvement of iron and free radical mediated lipid peroxidation injuries in AD pathogenesis is further supported by the recent discovery of ferroptosis, as a mode of necrotic cell death executed by an iron-catalyzed lipid peroxidation process. Preliminary data in the lab suggest that targeting Tau phosphorylation for example via ferroptosis-kinase pathways could represent a valid therapeutic approach to reduce Tau aggregation and associated neuronal death in AD and other neurodegenerative 'Tauopathies'. Our lab conceptualized ferroptosis induced by an excess in labile iron as non-canonical ferroptosis. In collaboration with the medicinal chemistry lab (Prof. K. Augustijns, UA), we also developed and characterized a novel generation of ferroptosis inhibitors. A lead candidate is superior over the benchmarks ferroptosis inhibitors in protecting against several ferroptosis-driven experimental disease models, including neurodegeneration in experimental multiple sclerosis. These novel class of inhibitors allows to determine the crosstalk of iron dependent lipid peroxidation with kinome signaling changes towards Tau phosphorylation and ferroptosis induced neurodegeneration. Within the current grant application, we want to identify ferroptosis dependent inhibition of Tau kinases by blocking ferroptosis in two cellular models of Alzheimer's disease using innovative phospho-peptidome kinome activity profiling, followed by kinobead-phosphoproteomic validation.

Keywords:EXPERIMENTAL STUDY

Disciplines:Cell death, Cell signalling, Neurological and neuromuscular diseases