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.
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