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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / metabolism*
  • Axons / metabolism
  • Cells, Cultured
  • Dendritic Spines / metabolism
  • Endocytosis / physiology*
  • Hippocampus / metabolism*
  • Metabolic Networks and Pathways / physiology*
  • Mice
  • Neurons / metabolism*
  • Optical Imaging
  • Presynaptic Terminals / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human