Amyloid-β and Alzheimer’s disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions

Abstract

The entorhinal–hippocampal circuit is severely affected in Alzheimer's disease (AD). Here, we demonstrate that amyloid-β (Aβ) differentially affects primary cultured astrocytes derived from the entorhinal cortex (EC) and from the hippocampus from non-transgenic controls and 3xTg-AD transgenic mice. Exposure to 100 nM of Aβ resulted in increased expression of the metabotropic glutamate receptor type 5 (mGluR5) and its downstream InsP3 receptor type 1 (InsP3R1) in hippocampal but not in EC astrocytes. Amplitudes of Ca2+ responses to an mGluR5 agonist, DHPG, and to ATP, another metabotropic agonist coupled to InsP3Rs, were significantly increased in Aβ-treated hippocampal but not in EC astrocytes. Previously we demonstrated that senile plaque formation in 3xTg-AD mice triggers astrogliosis in hippocampal but not in EC astrocytes. The different sensitivities of the Ca2+ signalling toolkit of EC versus hippocampal astrocytes to Aβ may account for the lack of astrogliosis in the EC, which in turn can explain the higher vulnerability of this region to AD.

Astroglial calcium signalling in Alzheimer's disease

“…Similar, high-frequency Ca 2+ waves were also monitored in astrocytes from APP Swe mice even before the formation of β-amyloid deposits [141]. In hippocampal astrocytes isolated and cultured from neonatal 3xTg-AD mice, the amplitude of ATP-induced [Ca 2+ ] i transients as well as the store-operated Ca 2+ entry were significantly increased [125,137]. In contrast, store-operated Ca 2+ entry in astrocytes from APP-over-expressing Tg5469 AD mice was not affected, although the deletion of APP inhibited SOCE, possibly due to down-regulation of Orai1 and TRPC1 channels [142].…”

“…After 48 hours of incubation with 100 nM of β-amyloid 1-42, a significant increase in the expression of mRNA for InsP 3 receptors type 1 and 2 (InsP 3 R1 and InsP 3 R2) was detected in rat hippocampal primary astrocytes [112]. In contrast, the same treatment did not affect the expression of InsP 3 R1 protein in the entorhinal cortex astrocytes, indicating a regional heterogeneity of astrocytes [125]. In human post-mortem tissues, however, an overall decrease in the expression of InsP 3 receptors is observed [133][134][135], which may, however, indicate the overall cell loss and, hence, a decrease in the total expression of receptors.…”

“…Already after 1 hour of incubation of cultured astrocytes with 100 nM of β-amyloid, it induced clustering and diffusional trapping of metabotropic glutamate receptor 5 (mGluR5); this in turn activated the receptor and induced release of ATP [124]. At longer exposure times (24-72 h), β-amyloid upregulated the expression of astroglial mGluR5 [125]. Incidentally, the up-regulation of mGluR5 has been also found in plaque-surrounding cortical astrocytes associated with senile plaques in the APPswe/PS1dE9 mouse model, as well as in post-mortem human tissues [112,113].…”

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…Ab 42 -induced Ca 2+ release from the ER includes an Ab 42 sequence-specific component, which is IP 3 R-dependent, and another component, which is peptide sequenceand IP 3 R-independent [115]. The effect of Ab 42 oligomers on IICR was studied in astrocytes derived from the entorhinal cortex and from the hippocampus from WT and 39 Tg-AD transgenic mice [116]. The treatment of WT astrocytes with Ab 42 increased the expression of IP 3 R1 and mGluR5 in hippocampal astrocytes and provoked IICR only in hippocampal and not entorhinal cortex astrocytes.…”

Neurodegeneration and Neuroglia: Emphasis on Astroglia in Alzheimer’s Disease

“…For example, extracellular β-amyloid triggers abnormal oscillatory Ca 2+ fluctuations in cultured primary astrocytes (Abramov et al 2003(Abramov et al , 2004. Incubating primary astrocytes with pathologically relevant concentrations of soluble β-amyloid affects the expression of Ca 2+ toolkit components; importantly, this remodeling differs for astrocytes derived from different brain regions (Grolla et al 2013). Similarly, exposure to β-amyloid was claimed to down-regulate glutamate uptake in astroglial cells in vitro (Matos et al 2008).…”