Kedia Shekhar, Ramakrishna Pratyush, Netrakanti Pallavi Rao, Singh Nivedita, Sisodia Sangram S, Jose Mini, Kumar Sathish, Mahadevan Anita, Ramanan Narendrakumar, Nadkarni Suhita, Nair Deepak
Centre for Neuroscience, Indian Institute of Science, Bangalore 560012, India.
Indian Institute of Science Education and Research, Pune 411008, India.
iScience. 2020 Dec 11;24(1):101924. doi: 10.1016/j.isci.2020.101924. eCollection 2021 Jan 22.
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 β (CTFβ) production, defining the heterogeneity of amyloidogenic processing at individual synapses, leading to long-term synaptic deficits as seen in AD.
尽管对淀粉样前体蛋白（APP）的差异蛋白水解有直观的见解，但通过淀粉样生成途径在单个突触处形成局部产物背后的随机性仍不清楚。在这里，我们表明，与突触功能区的周围环境相比，淀粉样生成机制的主要成分，即APP和分泌酶，被离散地组织成高局部浓度的纳米域。此外，借助多种阿尔茨海默病（AD）模型，我们证实这种淀粉样生成机制的离散纳米级化学图谱在兴奋性突触处发生了改变。此外，我们提供了源自兴奋性突触内吞区的单一囊泡中淀粉样生成过程的真实模型。因此，我们展示了突触纳米级组织随机性的改变如何导致C末端片段β（CTFβ）产生的动态范围，定义了单个突触处淀粉样生成过程的异质性，导致如AD中所见的长期突触缺陷。
