Amyloid-Beta Mediates Homeostatic Synaptic Plasticity

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$

Automated summary

Recent studies have shown that APP plays a crucial physiological role in synaptic plasticity, especially in homeostatic synaptic plasticity. Processing of APP through the amyloidogenic pathway may be important for maintaining brain homeostasis and brain states associated with increased amyloid-b levels.