Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aβ production

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Abstract

Understanding the mechanisms that control processing of the amyloid precursor protein (APP) to produce amyloid-β (Aβ) peptide represents a key area of Alzheimer's disease research. Here, we show that siRNA-mediated loss of calsyntenin-1 in cultured neurons alters APP processing to increase production of Aβ. We also show that calsyntenin-1 is reduced in Alzheimer's disease brains and that the extent of this reduction correlates with increased Aβ levels. Calsyntenin-1 is a ligand for kinesin-1 light chains and APP is transported through axons on kinesin-1 molecular motors. Defects in axonal transport are an early pathological feature in Alzheimer's disease and defective APP transport is known to increase Aβ production. We show that calsyntenin-1 and APP are co-transported through axons and that siRNA-induced loss of calsyntenin-1 markedly disrupts axonal transport of APP. Thus, perturbation to axonal transport of APP on calsyntenin-1 containing carriers induces alterations to APP processing that increase production of Aβ. Together, our findings suggest that disruption of calsyntenin-1-associated axonal transport of APP is a pathogenic mechanism in Alzheimer's disease.
Original languageEnglish
Article numberN/A
Pages (from-to)2845-2854
Number of pages10
JournalHuman Molecular Genetics
Volume21
Issue number13
Early online date20 Mar 2012
DOIs
Publication statusPublished - 1 Jul 2012

Keywords

  • ALZHEIMERS-DISEASE
  • NEURODEGENERATIVE DISEASES
  • INTRACELLULAR-TRANSPORT
  • INTERACTING PROTEIN
  • CYTOPLASMIC DOMAIN
  • MEMBRANE-PROTEINS
  • TRANSGENIC MICE
  • GOLGI NETWORK
  • APP
  • KINASE

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