摘要：SummaryDespite intuitive insights into differential proteolysis of amyloid precursor protein (APP), the stochasticity behind local product formation through amyloidogenic pathway at individual synapses remain unclear. Here, we show that the major components of amyloidogenic machinery namely, APP and secretases are discretely organized into nanodomains of high local concentration compared to their immediate environment in functional zones of the synapse. Additionally, with the aid of multiple models of Alzheimer's disease (AD), we confirm that this discrete nanoscale chemical map of amyloidogenic machinery is altered at excitatory synapses. Furthermore, we provide realistic models of amyloidogenic processing in unitary vesicles originating from the endocytic zone of excitatory synapses. Thus, we show how an alteration in the stochasticity of synaptic nanoscale organization contributes to the dynamic range of C-terminal fragments β (CTFβ) production, defining the heterogeneity of amyloidogenic processing at individual synapses, leading to long-term synaptic deficits as seen in AD.Graphical AbstractDisplay OmittedHighlights•Components of amyloidogenic machinery are organized into nanodomains•Assembly of nanodomains differs between functional zones of the synapse•Stochasticity of nanoscale organization dictates dynamic range of APP proteolysis•Variability in composition of amyloidogenic machinery is associated with ADCellular Neuroscience; Molecular Neuroscience; Optical Imaging
