期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 72, 期 4, 页码 1217-1231出版社
IOS PRESS
DOI: 10.3233/JAD-190796
关键词
Amyloid-beta; APP/PS1-AD mice; calcium overload; cognitive behavior; endoplasmic reticulum stress; Xestospongin C
资金
- National Natural Science Foundation of China [31471080, 31600865]
- Fund Program for Sanjin Scholars of Shanxi Province
- Shanxi Province Science Foundation for Excellent Young Scholars [201801D211005]
- Shanxi Province Innovation Foundation for Postgraduate [2018SY051]
- Fund for Shanxi 1331 Project Key Subjects Construction (1331KSC)
- Fund for Shanxi Key Subjects Construction (FSKSC)
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-beta (A beta)-induced endoplasmic reticulum (ER) stress and memory impairments in AD. Here we showed for the first time the neuroprotective effects of XestosponginC(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 (3 mu mol) via Alzet osmotic pumps for four weeks, followed by cognition tests, A beta plaque examination, andERstress-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 A beta 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 A beta(1-42)-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 IP3R, XeC might be considered as a novel therapeutic strategy in AD.
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