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Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression

Weyer, Sascha W. ; Zagrebelsky, Marta ; Herrmann, Ulrike ; Hick, Meike ; Ganß, Lennard ; Gobbert, Julia ; Gruber, Morna ; Altmann, Christine ; Korte, Martin ; Deller, Thomas ; Müller, Ulrike C.

In: Acta Neuropathologica Communications, 2 (2014), Nr. 36. pp. 1-15. ISSN 2051-5960

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Download (902kB) | Lizenz: Creative Commons LizenzvertragComparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression by Weyer, Sascha W. ; Zagrebelsky, Marta ; Herrmann, Ulrike ; Hick, Meike ; Ganß, Lennard ; Gobbert, Julia ; Gruber, Morna ; Altmann, Christine ; Korte, Martin ; Deller, Thomas ; Müller, Ulrike C. underlies the terms of Creative Commons Attribution 3.0 Germany

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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.

Item Type: Article
Journal or Publication Title: Acta Neuropathologica Communications
Volume: 2
Number: 36
Publisher: Biomed Central
Place of Publication: London
Date Deposited: 27 May 2015 08:50
Date: 2014
ISSN: 2051-5960
Page Range: pp. 1-15
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Medizinische Fakultät Heidelberg > Pathologisches Institut
Subjects: 570 Life sciences
610 Medical sciences Medicine
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