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

摘要

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 β1 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.—Sosa, L. J., Postma, N. L., Estrada-Bernal, A., Hanna, M., Guo, R., Busciglio, J., Pfenninger, K. H. Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome.