Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome

• Autores: Sosa, Lucas Javier; Postma, Nienke L.; Estrada-Bernal, Adriana; Hanna, M.; Guo, R.; Busciglio, Jorge; Pfenninger, Karl H.
• Año de publicación: 2014
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: BRAIN DEVELOPMENT; NEURODEVELOPMENTAL DISORDERS
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Amyloid precursor protein (APP), encoded on Hsa21, functions as a cell adhesion molecule (CAM) in axonal growth cones (GCs) of the developing brain. We show here that axonal GCs of human fetal Down syndrome (DS) neurons (and of a DS mouse model) overexpress APP protein relative to euploid controls. We investigated whether DS neurons generate an abnormal, APP-dependent GC phenotype in vitro. On laminin, which binds APP and 1 integrins (Itgb1), DS neurons formed enlarged and faster-advancing GCs compared to controls. On peptide matrices that bind APP only, but not on those binding exclusively Itgb1 or L1CAM, DS GCs were significantly enlarged (2.0-fold), formed increased close adhesions (1.8-fold), and advanced faster (1.4-fold). In assays involving alternating stripes of monospecific matrices, human control GCs exhibited no preference for any of the substrates, whereas DS GCs preferred the APP-binding matrix (cross-over decreased significantly from 48.2 to 27.2%). Reducing APP expression in DS GCs with siRNA normalized most measures of the phenotype, including substrate choice. These experiments show that human DS neurons exhibit an APP-dependent, abnormal GC phenotype characterized by increased adhesion and altered contact guidance. The results suggest that APP overexpression may perturb axonal pathfinding and circuit formation in developing DS brain.
Fil: Sosa, Lucas Javier. University Of Colorado Anschutz Medical Center, Aurora; Estados Unidos
Fil: Postma, Nienke L.. School of Medicine, Aurora; Estados Unidos
Fil: Estrada-Bernal, Adriana. School of Medicine, Aurora; Estados Unidos. University Of Colorado Anschutz Medical Center, Aurora; Estados Unidos
Fil: Hanna, M.. University of California at Irvine; Estados Unidos
Fil: Guo, R.. University of Colorado; Estados Unidos
Fil: Busciglio, Jorge. University of California at Irvine; Estados Unidos
Fil: Pfenninger, Karl H.. University Of Colorado Anschutz Medical Center, Aurora; Estados Unidos