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

Grolla, Ambra A.; Fakhfouri, Gohar; Balzaretti, G; Marcello, Elena; Gardoni, Fabrizio; Canonico, Pier Luigi; Luca, Monica Di; Genazzani, Armando A.; Lim, Dmitry

doi:10.1016/j.neurobiolaging.2012.05.005

Cited by 82 publications

(68 citation statements)

References 57 publications

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“…The issue of whether or not astrocytes can express β-secretase (BACE) and cleave AβPP to produce Aβ remains unclear, with a few studies reporting Aβ production by astrocytes under certain conditions [31–33]. We found that confluent astrocyte cultures, either before (7–8 DIV) or after purification (12–16 DIV), did not secrete detectable amounts of Aβ 42 (Fig.…”

Section: Resultsmentioning

confidence: 83%

Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients

Lee

Kosuri

Arancio

2013

JAD

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Amyloid-β (Aβ) peptides are constitutively produced in the brain throughout life via mechanisms that can be regulated by synaptic activity. Although Aβ has been extensively studied as the pathological plaque-forming protein species in Alzheimer’s disease (AD), little is known about the normal physiological function(s) and signaling pathway(s). We previously discovered that physiologically-relevant, low picomolar amounts of Aβ can enhance synaptic plasticity and hippocampal-dependent cognition in mice. In this study, we demonstrated that astrocytes are cellular candidates for participating in this type of Aβ signaling. Using calcium imaging of primary astrocyte cultures, we observed that picomolar amounts of Aβ peptides can enhance spontaneous intracellular calcium transient signaling. After application of 200 pM Aβ42 peptides, the frequency and amplitude averages of spontaneous cytosolic calcium transients were significantly increased. These effects were dependent on α7 nicotinic acetylcholine receptors (α7-nAChRs), as the enhancement effects were blocked by a pharmacological α7-nAChR inhibitor and in astrocytes from an α7 deficient mouse strain. We additionally examined evoked intercellular calcium wave signaling but did not detect significant picomolar Aβ-induced alterations in propagation parameters. Overall, these results indicate that at a physiologically-relevant low picomolar concentration, Aβ peptides can enhance spontaneous astrocyte calcium transient signaling via α7-nAChRs. Since astrocyte-mediated gliotransmission has been previously found to have neuromodulatory roles, Aβ peptides may have a normal physiological function in regulating neuron-glia signaling. Dysfunction of this signaling process may underlie glia-based aspects of AD pathogenesis.

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Section: Resultsmentioning

confidence: 83%

Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients

Lee

Kosuri

Arancio

2013

JAD

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“…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. Finally, a chronic treatment with β-amyloid was also reported to increase the store-operated Ca 2+ entry in astrocytes [136,137].…”

Section: Effects Of β-Amyloidmentioning

confidence: 95%

Astroglial calcium signalling in Alzheimer's disease

Verkhratsky

Rodriguez-Arellano

Parpura

et al. 2017

Biochemical and Biophysical Research Communications

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Neuroglial contribution to Alzheimer's disease (AD) is pathologically relevant and highly heterogeneous. Reactive astrogliosis and activation of microglia contribute to neuroinflammation, whereas astroglial and oligodendroglial atrophy affect synaptic transmission and underlie the overall disruption of the central nervous system (CNS) connectome. Astroglial function is tightly integrated with the intracellular ionic signalling mediated by complex dynamics of cytosolic concentrations of free Ca 2+ and Na + . Astroglial ionic signalling is mediated by plasmalemmal ion channels, mainly associated with ionotropic receptors, pumps and solute carrier transporters, and by intracellular organelles comprised of the endoplasmic reticulum and mitochondria. The relative contribution of these molecular cascades/organelles can be plastically remodelled in development and under environmental stress. In AD astroglial Ca 2+ signalling undergoes substantial reorganisation due to an abnormal regulation of expression of Ca 2+ handling molecular cascades.

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“…In keeping, recent studies in vitro confirmed that, under normal conditions, astrocytes possess the APP-processing machinery for generating Aβ peptide, i.e., APP itself, BACE1 and/or its close homolog BACE2. 76,80,81 Furthermore, Aβ peptide was described to transcriptionally regulate the expression of the astrocytic BACE1 via the calcineurin/nuclear factor of activated T cells 4 (NFAT4) or nuclear factor-κB (NF-κB) signaling pathways, 82,83 suggesting a feed-forward mechanism to maintain or amplify Aβ deposits in astrocytes. More controversial is the issue of reactive astroglia as some studies indicated that cultured astrocytes, activated with cytokine combinations, positively regulate β-secretase activity and Aβ secretion, 84 whereas others found opposite results.…”

Section: Alzheimer Diseasementioning

confidence: 99%