Amyloid beta deregulates astroglial mGluR5‐mediated calcium signaling via calcineurin and Nf‐kB

Abstract

The amyloid hypothesis of Alzheimer's disease (AD) suggests that soluble amyloid β (Aβ) is an initiator of a cascade of events eventually leading to neurodegeneration. Recently, we reported that Aβ deranged Ca(2+) homeostasis specifically in hippocampal astrocytes by targeting key elements of Ca(2+) signaling, such as mGluR5 and IP3 R1. In the present study, we dissect a cascade of signaling events by which Aβ deregulates glial Ca(2+) : (i) 100 nM Aβ leads to an increase in cytosolic calcium after 4-6 h of treatment; (ii) mGluR5 is increased after 24 h of treatment; (iii) this increase is blocked by inhibitors of calcineurin (CaN) and NF-kB. Furthermore, we show that Aβ treatment of glial cells leads to de-phosphorylation of Bcl10 and an increased CaN-Bcl10 interaction. Last, mGluR5 staining is augmented in hippocampal astrocytes of AD patients in proximity of Aβ plaques and co-localizes with nuclear accumulation of the p65 NF-kB subunit and increased staining of CaNAα. Taken together our data suggest that nanomolar [Aβ] deregulates Ca(2+) homeostasis via CaN and its downstream target NF-kB, possibly via the cross-talk of Bcl10 in hippocampal astrocytes.

Astroglial calcium signalling in Alzheimer's disease

“…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].…”

“…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]. As alluded to earlier, α7 nicotinic cholinoreceptor (α7nAChR) binds β -amyloid with high affinity and can be modulated by ιτ is [126].…”

“…[111]. In another study the effect of β-amyloid on resting Ca 2+ was even more profound; incubation of cultured rat hippocampal astrocytes with 100 nM oligomeric β-amyloid 1-42 for 4 -6 hours elevated increased resting [Ca 2+ ] i from ~50 nM to 100-150 nM [112]. However, longer exposures (48 hours) of cultured astrocytes to β-amyloid in concentrations ranging between 200 nM and 20 mM did not affect basal [Ca 2+ ] i levels [113,114].…”

“…The data on acute effects of β-amyloid on astroglial cells in vitro and in slices are controversial. While several laboratories reported that β-amyloid (at 100 nM -5 µM) concentrations triggered transient [Ca 2+ ] i increases or [Ca 2+ ] i oscillations [98,[115][116][117][118][119], others have not found acute [Ca 2+ ] i responses to β-amyloid [112][113][114]. This seemingly incongruent findings could possibly be attributed to variability of β-amyloid species used.…”

Calcineurin and glial signaling: neuroinflammation and beyond

“…Greater numbers of CN-positive astrocytes have been reported in the hippocampus of aged, β-amyloid (Aβ)-bearing transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice, particularly in the immediate vicinity of extracellular Aβ deposits [18]. A similar relationship between CN-positive astrocytes and Aβ pathology was shown in postmortem brain tissue obtained from human subjects diagnosed with Alzheimer’s disease (AD) [19-21]. Though closely associated with Aβ deposits, the expression of CN in astrocytes does not necessarily depend on the presence of Aβ.…”