Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer's disease and regulates axonal transport and processing of the amyloid precursor protein

Acta Neuropathol Commun. 2019 Dec 5;7(1):200. doi: 10.1186/s40478-019-0857-5.

Abstract

Damage to axonal transport is an early pathogenic event in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer's disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer's disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer's disease.

Keywords: Alzheimer’s disease; Amyloid precursor protein; Axonal transport; Calsyntenin-1; Drosophila melanogaster; Kinesin light chain; Kinesin-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amino Acid Sequence
  • Amyloid beta-Protein Precursor / analysis
  • Amyloid beta-Protein Precursor / biosynthesis*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Axonal Transport / physiology*
  • Drosophila melanogaster
  • Female
  • Frontal Lobe / chemistry
  • Frontal Lobe / metabolism
  • Frontal Lobe / pathology
  • HEK293 Cells
  • Humans
  • Male
  • Microtubule-Associated Proteins / analysis
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Phosphorylation / physiology
  • Rats
  • Serine / analysis
  • Serine / genetics
  • Serine / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Microtubule-Associated Proteins
  • kinesin light-chain proteins
  • Serine