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01-01-2015 | Original Paper

Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity

Authors: Meike Hick, Ulrike Herrmann, Sascha W. Weyer, Jan-Philipp Mallm, Jakob-Andreas Tschäpe, Marianne Borgers, Marc Mercken, Fabian C. Roth, Andreas Draguhn, Lutz Slomianka, David P. Wolfer, Martin Korte, Ulrike C. Müller

Published in: Acta Neuropathologica | Issue 1/2015

Abstract

The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission. Here, we generated animals with a conditional APP/APLP2 double knockout (cDKO) in excitatory forebrain neurons using NexCre mice. Electrophysiological recordings of adult NexCre cDKOs indicated a strong synaptic phenotype with pronounced deficits in the induction and maintenance of hippocampal LTP and impairments in paired pulse facilitation, indicating a possible presynaptic deficit. These deficits were also reflected in impairments in nesting behavior and hippocampus-dependent learning and memory tasks, including deficits in Morris water maze and radial maze performance. Moreover, while no gross alterations of brain morphology were detectable in NexCre cDKO mice, quantitative analysis of adult hippocampal CA1 neurons revealed prominent reductions in total neurite length, dendritic branching, reduced spine density and reduced spine head volume. Strikingly, the impairment of LTP could be selectively rescued by acute application of exogenous recombinant APPsα, but not APPsβ, indicating a crucial role for APPsα to support synaptic plasticity of mature hippocampal synapses on a rapid time scale. Collectively, our analysis reveals an essential role of APP family proteins in excitatory principal neurons for mediating normal dendritic architecture, spine density and morphology, synaptic plasticity and cognition.

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Title: Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity
Authors: Meike Hick
Ulrike Herrmann
Sascha W. Weyer
Jan-Philipp Mallm
Jakob-Andreas Tschäpe
Marianne Borgers
Marc Mercken
Fabian C. Roth
Andreas Draguhn
Lutz Slomianka
David P. Wolfer
Martin Korte
Ulrike C. Müller
Publication date: 01-01-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-014-1368-x

2024 ASCO Annual Meeting

Springer Medicine

Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity

Abstract

2024 ASCO Annual Meeting

Springer Medicine

Abstract

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