Amyloid-Beta Mediates Homeostatic Synaptic Plasticity.

Christos Galanis,Thomas Deller,Andreas Vlachos,Denise Becker,Stefan F Lichtenthaler,Ulrike C Müller,Meike Fellenz,Charlotte Bold

doi:10.1523/jneurosci.1820-20.2021

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 APP−/− 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 APP+/+ tissue treated with β- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca2+-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.

Highlights

In recent years, considerable effort has been directed to better understand the pathogenic role of the amyloid precursor protein (APP) and its cleavage products in neurodegeneration (Bohm et al, 2015)
Homeostatic synaptic plasticity is not observed in dentate granule cells of APP-deficient entorhinal-hippocampal tissue cultures with a cut off molecular weight of 10 kDa
This plasticity phenotype does not depend on APP secreted ectodomain a (APPsa), which is generated from APP via nonamyloidogenic processing and which has been linked to Hebbian plasticity, but on Ab, which is generated from APP via processing along the amyloidogenic pathway

Summary

Introduction

Considerable effort has been directed to better understand the pathogenic role of the amyloid precursor protein (APP) and its cleavage products in neurodegeneration (Bohm et al, 2015). Galanis et al · APP Processing and Synaptic Scaling al., 1999; Herms et al, 2004; Ring et al, 2007) have shed new light on the role of APP in neuronal migration, synaptogenesis, and synaptic structure and function (Müller et al, 2017). It has been proposed that APP could play an important role in neuronal structural and functional plasticity under physiological conditions through the “non-amyloidogenic pathway,” which produces APPsa. The physiological function of Ab has, remained enigmatic

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Results

Conclusion