title: Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome.
abstract: 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.
authors.affiliation: 3Department of Pediatrics, University of Colorado, Mailbox 8313, 12800 E. 19th Ave, Aurora, CO 80045, USA. karl.pfenninger@ucdenver.edu.
authors.forename: Lucas J
authors.initials: LJ
authors.lastname: Sosa
authors.forename: Nienke L
authors.initials: NL
authors.lastname: Postma
authors.forename: Adriana
authors.initials: A
authors.lastname: Estrada-Bernal
authors.forename: M
authors.initials: M
authors.lastname: Hanna
authors.forename: R
authors.initials: R
authors.lastname: Guo
authors.forename: Jorge
authors.initials: J
authors.lastname: Busciglio
authors.forename: Karl H
authors.initials: KH
authors.lastname: Pfenninger
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004314:Down Syndrome / Q000378:metabolism*; D020439:Growth Cones / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007797:Laminin / Q000378:metabolism; D051379:Mice
chemical_list: D016564:Amyloid beta-Protein Precursor; D015815:Cell Adhesion Molecules; D007797:Laminin
keywords: brain development; neurodevelopmental disorders
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