Human brain proteins showing neuron-specific interactions with γ-secretase

FEBS J. 2015 Jul;282(14):2587-99. doi: 10.1111/febs.13303. Epub 2015 Jul 2.


The transmembrane protease complex γ-secretase is a key enzyme in Alzheimer disease pathogenesis as it liberates the neurotoxic amyloid β-peptide (Aβ); however, the mechanism of regulation of its activity in various cell types and subcellular compartments is largely unknown. Several γ-secretase inhibitors have been developed, but none have been released due to side-effects that appear to arise from reduced processing of Notch, one of many γ-secretase substrates. Hence, it is desirable to specifically inhibit Aβ production. In our previous studies, we have identified several γ-secretase-associated proteins (GSAPs) from brain, which affect Aβ production without having any major effects on Notch processing. In the present study using detergent-resistant membranes prepared from brain, we have identified four GSAPs that affect Aβ production to a greater extent than Notch processing. We evaluated the interaction between GSAPs and γ-secretase in various cell types and their mRNA expression in various human organs. Using an in situ proximity ligation assay, we demonstrated that many GSAPs showed considerably greater interaction with γ-secretase in neurons than in human embryonic kidney cells stably over-expressing APP, and showed that several GSAPs are highly expressed in human brain. This study underscores the importance of studying protein-protein interactions in relevant cell types, and suggests that reducing Aβ production by interfering with brain- or neuron-specific γ-secretase/GSAP interactions may reduce the risk of unwanted side-effects associated with treatment of Alzheimer disease.

Keywords: Alzheimer disease; presenilin; protein interaction; proximity ligation assay; γ-secretase-associated protein.

Publication types

  • Editorial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism*
  • Cells, Cultured
  • GAP-43 Protein / genetics
  • GAP-43 Protein / metabolism
  • HEK293 Cells
  • Hippocampus / cytology
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Munc18 Proteins / genetics
  • Munc18 Proteins / metabolism
  • Neurons / metabolism*
  • Protein Interaction Mapping / methods
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Small Interfering
  • Receptors, Notch / metabolism


  • Amyloid beta-Peptides
  • GAP-43 Protein
  • Membrane Proteins
  • Munc18 Proteins
  • Proteins
  • RNA, Small Interfering
  • Receptors, Notch
  • STXBP1 protein, human
  • flotillins
  • Amyloid Precursor Protein Secretases