Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway.
Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway.
复制标题
DOI：
10.1038/nn.4188
复制
发表时间：
2016-01
影响因子：
25
通讯作者：
Roy S
中科院分区：
文献类型：
--
作者：
Das U;Wang L;Ganguly A;Saikia JM;Wagner SL;Koo EH;Roy S
Cleavage of APP (amyloid precursor protein) by BACE-1 (β-site APP cleaving enzyme-1) is the rate-limiting step in amyloid-beta (Aβ) production and a neuropathologic hallmark of Alzheimer's disease (AD); thus physical approximation of this substrate-enzyme pair is a critical event with broad biological and therapeutic implications. Despite much research, neuronal locales of APP/BACE-1 convergence and APP-cleavage remain unclear. Here we report an optical assay – based on fluorescence complementation – to visualize in-cellulo APP/BACE-1 interactions as a simple on/off signal. Combined with other assays tracking the fate of internalized APP in hippocampal neurons, we found that APP/BACE-1 interact in both biosynthetic and endocytic compartments; particularly along recycling-microdomains such as dendritic spines and presynaptic boutons. In axons, APP and BACE-1 are co-transported, and also interact during transit. Finally, our assay reveals that the AD-protective “Icelandic” mutation greatly attenuates APP/BACE-1 interactions, suggesting a mechanistic basis for protection. Collectively, the data challenge canonical models and provide concrete insights into long-standing controversies in the field.
