A new target for Alzheimer's disease: A small molecule SERCA activator is neuroprotective in vitro and improves memory and cognition in APP/PS1 mice

Bioorg Med Chem Lett. 2018 May 15;28(9):1591-1594. doi: 10.1016/j.bmcl.2018.03.052. Epub 2018 Mar 21.


Amongst the cellular cacophony of altered signals in Alzheimer's disease (AD), disrupted Ca2+ homeostasis and consequential endoplasmic reticulum (ER) stress signals have been recognized as key determinants of neuron fate. This altered Ca2+ state is accompanied by a failing sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump, which has been recognized as a causal feature of the underlying disease state. Repair of the Ca2+ dyshomeostasis represents a putative drug target via alleviation of ER stress and rescue of injured neurons, effectively modifying the AD state. Herein, we report a small molecule SERCA activator that rescues brain cells and raises ER Ca2+ in vitro, and shows efficacy in the APP/PS1 double transgenic mouse model of Alzheimer's disease. These results support SERCA activation as a therapeutic target for AD.

Keywords: Alzheimer’s disease; Drug discovery; ER stress; Medicinal chemistry; Neurodegeneration; SERCA; Small molecules.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Animals
  • Cognition / drug effects*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Memory / drug effects*
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Neuroprotective Agents
  • Small Molecule Libraries
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases