Xestospongin C, a Reversible IP3 Receptor Antagonist, Alleviates the Cognitive and Pathological Impairments in APP/PS1 Mice of Alzheimer's Disease

Exaggerated Ca2+ signaling might be one of primary causes of neural dysfunction in Alzheimer's disease (AD). And the intracellular Ca2+ overload has been closely associated with Amyloid-β (Aβ)-induced endoplasmic reticulum (ER) stress and memory impairments in AD. Here we showed for the first time the neuroprotective effects of Xestospongin C (XeC), a reversible IP3 receptor antagonist, on the cognitive behaviors and pathology of APP/PS1 AD mice. Male APP/PS1-AD mice (n = 20) were injected intracerebroventricularly with XeC (3μmol) via Alzet osmotic pumps for four weeks, followed by cognition tests, Aβ plaque examination, and ER stress-related protein measurement. The results showed that XeC pretreatment significantly improved the cognitive behavior of APP/PS1-AD mice, raising the spontaneous alteration accuracy in Y maze, decreasing the escape latency and increasing the target quadrant swimming time in Morris water maze; XeC pretreatment also reduced the number of Aβ plaques and the overexpression of ER stress proteins 78 kDa glucose-regulated protein (GRP-78), caspase-12, and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) in the hippocampus of APP/PS1 mice. In addition, in vitro experiments showed that XeC effectively ameliorated Aβ1 - 42-induced early neuronal Apoptosis and intracellular Ca2+ overload in the primary hippocampal neurons. Taken together, IP3R-mediated Ca2+ disorder plays a key role in the cognitive deficits and pathological damages in AD mice. By targeting the IP3 R, XeC might be considered as a novel therapeutic strategy in AD.