title: Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aβ production.
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.
authors.affiliation: KCL Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, King’s College London, De Crespigny Park, London, UK
authors.forename: Alessio
authors.initials: A
authors.lastname: Vagnoni
authors.forename: Michael S
authors.initials: MS
authors.lastname: Perkinton
authors.forename: Emma H
authors.initials: EH
authors.lastname: Gray
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
mesh_terms: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; C513820:Clstn1 protein, rat; D008562:Membrane Glycoproteins; D053764:Presenilin-1; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; C413604:nicastrin protein; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C542371:ADAM10 protein, rat; D016547:Kinesins