Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention

J Exp Med. 2021 Apr 5;218(4):e20202560. doi: 10.1084/jem.20202560.


A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / prevention & control*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Female
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Peptide Fragments / metabolism
  • Phenethylamines / administration & dosage*
  • Pyridazines / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Treatment Outcome


  • Amyloid beta-Peptides
  • BPN-15606
  • Peptide Fragments
  • Phenethylamines
  • Pyridazines
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases