@article{959d35542cd44766b9428a3aa72ab5a8,
title = "Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice",
abstract = "Mushroom dendritic spine structures are essential for memory storage, and the loss of mushroom spines may explain memory defects in Alzheimer's disease (AD). Here we show a significant reduction in the fraction of mushroom spines in hippocampal neurons from the presenilin-1 M146V knockin (KI) mouse model of familial AD (FAD). The stabilization of mushroom spines depends on STIM2-mediated neuronal store-operated calcium influx (nSOC) and continuous activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII). We demonstrate that STIM2-nSOC-CaMKII pathway is compromised in KI neurons, in aging neurons, and in sporadic AD brains due to downregulation of STIM2 protein. We further establish that overexpression of STIM2 rescues synaptic nSOC, CaMKII activity, and mushroom spine loss in KI neurons. Our results identify STIM2-nSOC-CaMKII synaptic maintenance pathway as a novel potential therapeutic target for treatment of AD and age-related memory decline.",
author = "Suya Sun and Hua Zhang and Jie Liu and Elena Popugaeva and Xu, {Nan Jie} and Stefan Feske and White, {Charles L.} and Ilya Bezprozvanny",
note = "Funding Information: We are grateful to Hui Zheng for providing PS1-M146V KI mice, to Mathias Jucker for APPPS1 mice, to Lin Tian for providing Gcamp5.3 plasmid, to Thomas S{\"u}dhof for providing Lenti-Cre constructs, to Xia Liang for technical assistance, to Leah Taylor for administrative assistance, and to Robin Hiesinger, Jen Liou, and Ege Kavalali for comments on the manuscript. We thank Dr. Beverly Davidson, Maria L. Scheel, and the staff of the University of Iowa Gene Transfer Vector Core for help with AAV production. We are grateful to Dr. Roger Rosenberg, Mr. Chan Foong, and Ms. Ellen Suen for help with collection and analysis of human clinical samples. I.B. is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer{\textquoteright}s Disease Research. This work was supported by McKnight Brain Disorders Award (I.B.); by Welch Foundation grant I-1754 (I.B.); by NIH grants R01NS080152 (I.B.), R01AI097302 (S.F.), and P30 AG12300 (C.W.); by the contract with the Russian Ministry of Science 11.G34.31.0056 (I.B.); and by the Shanghai Committee of Science and Technology (11DZ2260200) (N.J.X.), China 973 Program (2014CB965002) (N.J.X.), Pujiang Program (13PJ1405500) (N.J.X.), and National Natural Science Foundation of China grants 91232704 and 31271160 (N.J.X.). ",
year = "2014",
month = apr,
day = "2",
doi = "10.1016/j.neuron.2014.02.019",
language = "English (US)",
volume = "82",
pages = "79--93",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",
}