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.

Amongst the cellular cacophony of altered signals in Alzheimer's disease (AD), disrupted Ca homeostasis and consequential endoplasmic reticulum (ER) stress signals have been recognized as key determinants of neuron fate. This altered Ca state is accompanied by a failing sarco/endoplasmic reticulum Ca-ATPase (SERCA) pump, which has been recognized as a causal feature of the underlying disease state. Repair of the Ca 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 Ca 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.