Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer's disease

Despite 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 beta (CTF beta) production, defining the heterogeneity of amyloidogenic processing at individual synapses, leading to long-term synaptic deficits as seen in AD.

Automated summary

Through studying the distribution of major components of the amyloidogenic machinery at synaptic functional zones and investigating various Alzheimer's disease models, it was found that the nanoscale chemical map of amyloidogenic machinery is altered at excitatory synapses. Alterations in the stochasticity of synaptic nanoscale organization contribute to the dynamic range of CTF beta production, defining the heterogeneity of amyloidogenic processing at individual synapses and leading to long-term synaptic deficits in AD.