Aβ leads to Ca2+ signaling alterations and transcriptional changes in glial cells

The pathogenesis of Alzheimer's disease includes accumulation of toxic amyloid beta (A beta) peptides. A recently developed cell-permeable peptide, termed Tat-Pro, disrupts the complex between synapse-associated protein 97 (SAP97) and the alpha-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), thereby leading to an alteration of the trafficking of the enzyme, which is important for nonamyloidogenic processing of amyloid precursor protein (APP). We report that Tat-Pro treatment, as well as the treatment with exogenous A beta, deregulates Ca2+ homeostasis specifically in astrocytes through increased expression of key components of Ca2+ signaling, metabotropic glutamate receptor-5 and inositol 1,4,5-trisphosphate receptor-1. This is accompanied by potentiation of (S)-3,5-dihydroxyphenylglycine-induced Ca2+ transients. Calcineurin inhibition reverts all these effects. Furthermore, our data demonstrate that astrocytes express all the components for the amyloidogenic and nonamyloidogenic processing of APP including APP itself, beta-site APP-cleaving enzyme 1 (BACE1), ADAM10, gamma-secretase, and SAP97. Indeed, treatment with Tat-Pro for 48 hours significantly increased the amount of A beta(1-42) in the medium of cultured astrocytes. Taken together, our results suggest that astroglia might be active players in A beta production and indicate that the calcium hypothesis of Alzheimer's disease may recognize glial cells as important intermediates. (C) 2013 Elsevier Inc. All rights reserved.