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Background  The intermediate-conductance Ca 2+ -activated K +  channel KCa3.1 was recently shown to control the phenotype switch of reactive astrogliosis (RA) in Alzheimer’s disease (AD).    Methods  KCa3.1 channels expression and cell localization in the brains of AD patients and APP/PS1 mice model were measured by immunoblotting and immunostaining. APP/PS1 mice and KCa3.1 −/− /APP/PS1 mice were subjected to Morris water maze test to evaluate the spatial memory deficits. Glia activation and neuron loss was measured by immunostaining. Fluo-4AM was used to measure cytosolic Ca 2+  level in β-amyloid (Aβ) induced reactive astrocytes in vitro.    Results  KCa3.1 expression was markedly associated with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in both Aβ-stimulated primary astrocytes and brain lysates of AD patients and APP/PS1 AD mice. The KCa3.1 channel was shown to regulate store-operated Ca 2+  entry (SOCE) through an interaction with the Ca 2+  channel Orai1 in primary astrocytes. Gene deletion or pharmacological blockade of KCa3.1 protected against SOCE-induced Ca 2+  overload and ER stress via the protein kinase B (AKT) signaling pathway in astrocytes. Importantly, gene deletion or blockade of KCa3.1 restored AKT/mechanistic target of rapamycin signaling both in vivo and in vitro. Consistent with these in vitro data, expression levels of the ER stress markers 78-kDa glucose-regulated protein and CCAAT/enhancer-binding protein homologous protein, as well as that of the RA marker glial fibrillary acidic protein were increased in APP/PS1 AD mouse model. Elimination of KCa3.1 in KCa3.1 −/− /APP/PS1 mice corrected these abnormal responses. Moreover, glial activation and neuroinflammation were attenuated in the hippocampi of KCa3.1 −/− /APP/PS1 mice, as compared with APP/PS1 mice. In addition, memory deficits and neuronal loss in APP/PS1 mice were reversed in KCa3.1 −/− /APP/PS1 mice.    Conclusions  Overall, these results suggest that KCa3.1 is involved in the regulation of Ca 2+  homeostasis in astrocytes and attenuation of the UPR and ER stress, thus contributing to memory deficits and neuronal loss.

Ca2+-dependent endoplasmic reticulum stress correlation with astrogliosis involves upregulation of KCa3.1 and inhibition of AKT/mTOR signaling