ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES(2020)
摘要
Senile plaques, the hallmarks of Alzheimer's Disease (AD), are generated by the deposition of amyloid-beta (A beta), the proteolytic product of amyloid precursor protein (APP), by beta and gamma-secretase. A large body of evidence points towards a role for Ca(2+)imbalances in the pathophysiology of both sporadic and familial forms of AD (FAD). A reduction in store-operated Ca(2+)entry (SOCE) is shared by numerous FAD-linked mutations, and SOCE is involved in A beta accumulation in different model cells. In neurons, both the role and components of SOCE remain quite obscure, whereas in astrocytes, SOCE controls their Ca2+-based excitability and communication to neurons. Glial cells are also directly involved in A beta production and clearance. Here, we focus on the role of ORAI2, a key SOCE component, in modulating SOCE in the human neuroglioma cell line H4. We show that ORAI2 overexpression reduces both SOCE level and stores Ca(2+)content, while ORAI2 downregulation significantly increases SOCE amplitude without affecting store Ca(2+)handling. In A beta-secreting H4-APPswe cells, SOCE inhibition by BTP2 and SOCE augmentation by ORAI2 downregulation respectively increases and decreases A beta 42 accumulation. Based on these findings, we suggest ORAI2 downregulation as a potential tool to rescue defective SOCE in AD, while preventing plaque formation.
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关键词
Alzheimer's Disease,amyloid-beta,neuroglioma cells,ORAI2,calcium entry,stores,SOCE
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