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  • Title: Modification of astrocytic Cx43 hemichannel activity in animal models of AD: modulation by adenosine A2A receptors.
    Author: Madeira D, Domingues J, Lopes CR, Canas PM, Cunha RA, Agostinho P.
    Journal: Cell Mol Life Sci; 2023 Oct 29; 80(11):340. PubMed ID: 37898985.
    Abstract:
    Increasing evidence implicates astrocytic dysfunction in Alzheimer's disease (AD), a neurodegenerative disorder characterised by progressive cognitive loss. The accumulation of amyloid-β (Aβ) plaques is a histopathological hallmark of AD and associated with increased astrocyte reactivity. In APP/PS1 mice modelling established AD (9 months), we now show an altered astrocytic morphology and enhanced activity of astrocytic hemichannels, mainly composed by connexin 43 (Cx43). Hemichannel activity in hippocampal astrocytes is also increased in two models of early AD: (1) mice with intracerebroventricular (icv) administration of Aβ1-42, and (2) hippocampal slices superfused with Aβ1-42 peptides. In hippocampal gliosomes of APP/PS1 mice, Cx43 levels were increased, whereas mice administered icv with Aβ1-42 only displayed increased Cx43 phosphorylation levels. This suggests that hemichannel activity might be differentially modulated throughout AD progression. Additionally, we tested if adenosine A2A receptor (A2AR) blockade reversed alterations of astrocytic hemichannel activity and found that the pharmacological blockade or genetic silencing (global and astrocytic) of A2AR prevented Aβ-induced hemichannel dysregulation in hippocampal slices, although A2AR genetic silencing increased the activity of astroglial hemichannels in control conditions. In primary cultures of astrocytes, A2AR-related protective effect was shown to occur through a protein kinase C (PKC) pathway. Our results indicate that the dysfunction of hemichannel activity in hippocampal astrocytes is an early event in AD, which is modulated by A2AR.
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