title: Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression.
abstract: Synaptic dysfunction and synapse loss are key features of Alzheimer's pathogenesis. Previously, we showed an essential function of APP and APLP2 for synaptic plasticity, learning and memory. Here, we used organotypic hippocampal cultures to investigate the specific role(s) of APP family members and their fragments for dendritic complexity and spine formation of principal neurons within the hippocampus. Whereas CA1 neurons from APLP1-KO or APLP2-KO mice showed normal neuronal morphology and spine density, APP-KO mice revealed a highly reduced dendritic complexity in mid-apical dendrites. Despite unaltered morphology of APLP2-KO neurons, combined APP/APLP2-DKO mutants showed an additional branching defect in proximal apical dendrites, indicating redundancy and a combined function of APP and APLP2 for dendritic architecture. Remarkably, APP-KO neurons showed a pronounced decrease in spine density and reductions in the number of mushroom spines. No further decrease in spine density, however, was detectable in APP/APLP2-DKO mice. Mechanistically, using APPsα-KI mice lacking transmembrane APP and expressing solely the secreted APPsα fragment we demonstrate that APPsα expression alone is sufficient to prevent the defects in spine density observed in APP-KO mice. Collectively, these studies reveal a combined role of APP and APLP2 for dendritic architecture and a unique function of secreted APPs for spine density.
authors.forename: Sascha W
authors.initials: SW
authors.lastname: Weyer
authors.forename: Marta
authors.initials: M
authors.lastname: Zagrebelsky
authors.forename: Ulrike
authors.initials: U
authors.lastname: Herrmann
authors.forename: Meike
authors.initials: M
authors.lastname: Hick
authors.forename: Lennard
authors.initials: L
authors.lastname: Ganss
authors.forename: Julia
authors.initials: J
authors.lastname: Gobbert
authors.forename: Morna
authors.initials: M
authors.lastname: Gruber
authors.forename: Christine
authors.initials: C
authors.lastname: Altmann
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.affiliation: Department of Bioinformatics and Functional Genomics, Ruprecht-Karls University Heidelberg, Institute of Pharmacy and Molecular Biotechnology, Im Neuenheimer Feld 364, Heidelberg D-69120, Germany. u.mueller@urz.uni-heidelberg.de.
authors.forename: Ulrike C
authors.initials: UC
authors.lastname: Müller
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000172:deficiency* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D049229:Dendritic Spines / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000648:ultrastructure*; D009924:Organ Culture Techniques; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; C492952:Aplp2 protein, mouse