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Nat Neurosci. 2016 Jan;19(1):55-64. doi: 10.1038/nn.4188. Epub 2015 Dec 7.

Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway.

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Department of Pathology, University of California, San Diego, La Jolla, California, USA.
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
Department of Medicine and Physiology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore.


Cleavage of amyloid precursor protein (APP) by BACE-1 (β-site APP cleaving enzyme-1) is the rate-limiting step in amyloid-β (Aβ) production and a neuropathologic hallmark of Alzheimer's disease; thus, physical approximation of this substrate-enzyme pair is a crucial event with broad biological and therapeutic implications. Despite much research, neuronal locales of APP and BACE-1 convergence and APP cleavage remain unclear. Here we report an optical assay, based on fluorescence complementation, for visualizing in cellulo APP-BACE-1 interactions as a simple on/off signal. Combining this with other assays tracking the fate of internalized APP in hippocampal neurons, we found that APP and BACE-1 interacted in both biosynthetic and endocytic compartments, particularly along recycling microdomains such as dendritic spines and presynaptic boutons. In axons, APP and BACE-1 were cotransported, and they also interacted during transit. Finally, our assay revealed that the Alzheimer's disease-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.

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