KIF2A downregulation links amyloid-β to Tau phosphorylation in Alzheimer's disease.

Abstract

Microtubules are essential components of the cytoskeleton. Dysfunctions of microtubules and microtubule-associated proteins are prominent features of neurodegenerative disorders. In Alzheimer's disease, changes in microtubule composition and hyperphosphorylation of Tau are more closely related to neurodegeneration than amyloid plaque formation. However, the accumulation of amyloid beta (Aβ) species is the earliest event in Alzheimer's disease pathology and induces Tau toxicity. KIF2A is a microtubule depolarizing kinesin with important roles during cortical development. KIF2A expression is maintained in the mature brain, where it is required for neuronal survival. Here, we used a conditional approach to ablate KIF2A specifically in the adult mouse cortex and hippocampus to assess the impact of KIF2A deletion on neuronal survival and Tau phosphorylation. We found that KIF2A deficiency leads to a reduction of dendritic spine density and maturation associated with cognitive decline, followed by an increase in Tau phosphorylation through MAPK ERK1/2 upregulation. We also studied KIF2A expression in a 5xFAD mouse model and post-mortem human brain tissue. We report that Aβ accumulation alters KIF2A expression in neurons and most importantly, KIF2A protein levels are drastically reduced in patients with Alzheimer's disease, but not in patients with other primary tauopathies. Our results shed light on the relationship between Aβ accumulation, KIF2A deregulation, microtubule dysfunction and enhanced Tau phosphorylation in the context of Alzheimer's disease.