Differential deregulation of astrocytic calcium signalling by arnyloid-β, TNFα, IL-1β. and LPS

In Alzheimer's disease (AD), astrocytes undergo complex morphological and functional changes that include early atrophy, reactive activation and Ca2+ deregulation. Recently, we proposed a mechanism by which nanomolar A beta(42) deregulates mGluR5 and InsP(3) receptors, the key elements of astrocytic Ca2+ signalling toolkit. To evaluate the specificity of these changes, we have now investigated whether the effects of A beta(42) on Ca2+ signalling machinery can be reproduced by pro-inflammatory agents (TNE alpha, IL-1 beta, LPS). Here we report that A beta(42) (100 nM, 72 h) significantly increased mRNA levels of mGluR5, InsP(3)R1 and InsP(3)R2, whereas pro-inflammatory agents reduced expression of these specific mRNAs. Furthermore, DHPG-induced Ca2+ signals and store operated Ca2+ entry (SOCE) were augmented in A beta(42)-treated cells due to up-regulation of a set of Ca2+ signalling-related genes including TRPC1 and TRPC4. Opposite changes were observed when astrocytes were treated with TNE alpha, IL-1 beta and LPS. Last, the effects observed on SOCE by treating wild-type astrocytes with A beta(42) were also identified in untreated astrocytes from 3 x Tg-AD animals, suggesting a link to the AD pathology. Our results demonstrate that effects of A beta(42) on astrocytic Ca2+ signalling differ from and may contrast to the effects of pro-inflammatory agents. (C) 2014 Elsevier Ltd. All rights reserved.