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

Ruiz Reig, Nuria;Virosztek, Margaux;Chehade, Georges;Suelves Caballol, Nuria;Tissir, Fadel;et.al.
(2025) Brain : a journal of neurology — (2025)

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Abstract
Microtubules (MT) are essential components of the cytoskeleton. Dysfunctions of MT and MT-associated proteins are prominent features of neurodegenerative disorders. In Alzheimer's disease (AD), changes in MT 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 AD 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 ERK1/2 activation. We also studied KIF2A expression in 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 AD patients 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 AD. Keywords: Alzheimer’s disease; microtubules; neurodegeneration; tau phosphorylation.
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Ruiz Reig, N., Virosztek, M., Chehade, G., Suelves Caballol, N., Zola, N. K. N., Salman, Y., Schakman, O., Kienlen-Campard, P., Hanseeuw, B., & Tissir, F. (2025). KIF2A downregulation links amyloid-β to Tau phosphorylation in Alzheimer’s disease. Brain : a journal of neurology. Accepted/in-press. https://doi.org/10.1093/brain/awaf382 (Original work published 2025)