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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.

Author information

1
Department of Pathology, University of California, San Diego, La Jolla, California, USA.
2
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
3
Department of Medicine and Physiology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore.

Abstract

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.

PMID:
26642089
PMCID:
PMC4782935
DOI:
10.1038/nn.4188
[Indexed for MEDLINE]
Free PMC Article

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