Amyloid-Beta Mediates Homeostatic Synaptic Plasticity
Christos Galanis, Meike Fellenz, Denise Becker, Charlotte Bold, Stefan F. Lichtenthaler, Ulrike Müller, Thomas Deller, Andreas Vlachos
Abstract
The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from <i>APP</i><sup>−/−</sup> mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-β and not by APPsα, and it is neither observed in <i>APP<sup>+/+</sup></i> tissue treated with β- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca<sup>2+</sup>-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increased amyloid-β levels.