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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 APPs? 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 APPs?-KI mice lacking transmembrane APP and expressing solely the secreted APPs? fragment we demonstrate that APPs? 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.

SUBMITTER: Weyer SW 

PROVIDER: S-EPMC4023627 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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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 SW   Zagrebelsky Marta M   Herrmann Ulrike U   Hick Meike M   Ganss Lennard L   Gobbert Julia J   Gruber Morna M   Altmann Christine C   Korte Martin M   Deller Thomas T   Müller Ulrike C UC  

Acta neuropathologica communications 20140331


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  ...[more]

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