Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool

Cell. 2016 Jun 30;166(1):193-208. doi: 10.1016/j.cell.2016.05.020. Epub 2016 Jun 9.


γ-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing γ-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex. Accordingly, PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer Aβ further. Moreover, a subset of FAD mutants in PSEN1, normally more broadly distributed in the cell, phenocopies PSEN2 and shifts its localization to late endosomes/lysosomes. Thus, localization of γ-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone Aβ42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 1 / metabolism
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amino Acid Motifs
  • Amyloid Precursor Protein Secretases / analysis*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cell Line, Tumor
  • Endosomes / chemistry
  • Humans
  • Lysosomes / chemistry
  • Mice
  • Peptide Fragments / metabolism*
  • Presenilin-1 / analysis
  • Presenilin-1 / chemistry
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Presenilin-2 / analysis*
  • Presenilin-2 / chemistry
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism
  • Rats
  • Substrate Specificity


  • Adaptor Protein Complex 1
  • Amyloid beta-Peptides
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Presenilin-2
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases