Abstract
Senile plaques, the hallmarks of Alzheimer’s Disease (AD), are generated by the deposition of amyloid-beta (Aβ), the proteolytic product of amyloid precursor protein (APP), by β and γ-secretase. A large body of evidence points towards a role for Ca2+ imbalances in the pathophysiology of both sporadic and familial forms of AD (FAD). A reduction in store-operated Ca2+ entry (SOCE) is shared by numerous FAD-linked mutations, and SOCE is involved in Aβ 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 Aβ 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 Ca2+ content, while ORAI2 downregulation significantly increases SOCE amplitude without affecting store Ca2+ handling. In Aβ-secreting H4-APPswe cells, SOCE inhibition by BTP2 and SOCE augmentation by ORAI2 downregulation respectively increases and decreases Aβ42 accumulation. Based on these findings, we suggest ORAI2 downregulation as a potential tool to rescue defective SOCE in AD, while preventing plaque formation.
Highlights
Both the familial (FAD) and sporadic (SAD) forms of Alzheimer’s Disease (AD) are characterized by abnormal accumulation of Aβ which leads to the formation of amyloid deposits, the so-called senile plaques, culminating in synaptic dysfunctions, inflammation and neuronal death [1,2,3]
We focus on the human neuroglioma cell line H4 and its clone H4-APPswe that stably expresses the forms of AD (FAD)-linked amyloid precursor protein (APP) Swedish mutation
We suggest ORAI2 as a novel therapeutic target in AD because its downregulation allows for the rescue of store-operated Ca2+ entry (SOCE) reduction, and at the same time, it reduces Aβ42 secretion by glial cells
Summary
Both the familial (FAD) and sporadic (SAD) forms of AD are characterized by abnormal accumulation of Aβ which leads to the formation of amyloid deposits, the so-called senile plaques, culminating in synaptic dysfunctions, inflammation and neuronal death [1,2,3]. Aβ is the product of APP proteolysis performed by two enzymes belonging to the secretase family. The last proteolytic cleavage, leading to Aβ production, is due to either presenilin-1 (PS1) or presenilin-2 (PS2), whose mutations, together with those of APP, are linked to FAD [4]. The enzyme, comprising either PS1 or PS2, called γ-secretase, produces several proteolytic variants of the Aβ peptide, among which Aβ40 and Aβ42 are the most common isoforms [1,2,3]. SOCE inhibition and activation were respectively linked to Aβ augmentation and decrement [7,23,24], whereas other groups reported that SOCE activation induces Aβ42 accumulation [25,26,27]
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