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DYRK1A ACTIVITY ROLE IN MICROTUBULE-BASED DYNAMICS REGULATES THE RETROGRADE AXONAL TRANSPORT OF APP IN HUMAN-DERIVED NEURONS
Abstract
Aims
DYRK1A triplication in Down Syndrome and its overexpression in Alzheimer Disease (AD) support a synergistic neurodegenerative effect in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of AD, which leads to APP processing impairments. However, whether DYRK1A regulates the intracellular transport and delivery of APP in mature neurons remains unknown. We propose to unravel the molecular mechanisms mediated by DYRK1A that control axonal transport dynamics of APP.
Methods
A protocol to obtain highly polarised human derived neurons in culture is used to pharmacologically inhibit DYRK1A activity or to overexpress DYRK1A kinase in oreder to perform high resolution/speed images to register the axonal transport of fluorescently labeled vesicles using the amyloid precursor protein fused to YFP. Matlab algortihms and routines were used to extract deep axonal transport parameters.
Results
Live-imaging in harmine-treated human-derived neurons showed reduced distal loading of APP vesicles and increased its stochastic retrograde axonal transport. Contrarily, DYRK1A overexpression increased the retrograde loading and processivity of APP vesicles. DYRK1A inhibition or overexpression showed no changes in vesicle speed transitions, however, modified the fraction and speed of retrograde segmental velocities suggesting a selective modulation of dynein motor activity.
Conclusions
We propose DYRK1A as a relevant modulator of APP metabolism through the control of its transport towards the soma and stress DYRK1A inhibition as a therapeutic intervention to restore axonal transport in AD