ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells

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.