Amyloid-Beta Mediates Homeostatic Synaptic Plasticity

Galanis, Christos; Fellenz, Meike; Becker, Denise; Bold, Charlotte; Lichtenthaler, Stefan F.; Mueller, Ulrike C.; Deller, Thomas und Vlachos, Andreas (2021): Amyloid-Beta Mediates Homeostatic Synaptic Plasticity. In: Journal of Neuroscience, Bd. 41, Nr. 24: S. 5157-5172

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 APPsa 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-b and not by APPsa, and it is neither observed in APP+/+ tissue treated with b-or c-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-b levels. Considerable effort has been directed to better understand the pathogenic role of the amyloid precursor protein (APP) and its cleavage products in neurodegeneration, with a major focus on the accumulation and deposition of synaptotoxic amyloid$ (A$) peptides, which are produced by sequential cleavage of APP by $ - and y-secretases. Although the amyloidogenic APP processing pathway has recently been targeted in patients with Alzheimer's disease, the physiological role of APP/A$

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198