Neurons are morphologically unique cells that rely on axonal transport for their function and viability. Amyloid-β oligomers (AβOs), a neurotoxin in Alzheimer’s disease (AD), disrupt axonal transport via dysregulation of signaling cascades. I assessed the role for glycogen synthase kinase 3β (GSK3β), a kinase implicated in AD, in the direct regulation of the kinesin KIF1A. Inhibition of GSK3β prevented transport defects in AβO-treated primary neurons, and co-immunoprecipitation studies confirmed an interaction between KIF1A and GSK3β. Mass spectrometry on KIF1A isolated from AD transgenic mouse brain (Tg2576) showed that within a regulatory domain, Ser 402 is phosphorylated and conforms to a GSK3β recognition site. The transport of a phospho-resistant (S402A) form of KIF1A was unaffected in AβO-treated neurons whereas KIF1A (S402E) transport is severely reduced. These data suggest that AβOs impair transport via GSK3β acting directly on KIF1A. Ultimately, this work may identify novel mechanisms of KIF1A regulation in AD.
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Thesis advisor: Silverman, Michael
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