PMID- 37898985
OWN - NLM
STAT- MEDLINE
DCOM- 20231031
LR  - 20231113
IS  - 1420-9071 (Electronic)
IS  - 1420-682X (Print)
IS  - 1420-682X (Linking)
VI  - 80
IP  - 11
DP  - 2023 Oct 29
TI  - Modification of astrocytic Cx43 hemichannel activity in animal models of AD: 
      modulation by adenosine A(2A) receptors.
PG  - 340
LID - 10.1007/s00018-023-04983-6 [doi]
LID - 340
AB  - Increasing evidence implicates astrocytic dysfunction in Alzheimer's disease 
      (AD), a neurodegenerative disorder characterised by progressive cognitive loss. 
      The accumulation of amyloid-beta (Abeta) 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 
      Abeta(1-42), and (2) hippocampal slices superfused with Abeta(1-42) peptides. In 
      hippocampal gliosomes of APP/PS1 mice, Cx43 levels were increased, whereas mice 
      administered icv with Abeta(1-42) only displayed increased Cx43 phosphorylation 
      levels. This suggests that hemichannel activity might be differentially modulated 
      throughout AD progression. Additionally, we tested if adenosine A(2A) receptor 
      (A(2A)R) blockade reversed alterations of astrocytic hemichannel activity and 
      found that the pharmacological blockade or genetic silencing (global and 
      astrocytic) of A(2A)R prevented Abeta-induced hemichannel dysregulation in 
      hippocampal slices, although A(2A)R genetic silencing increased the activity of 
      astroglial hemichannels in control conditions. In primary cultures of astrocytes, 
      A(2A)R-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 A(2A)R.
CI  - (c) 2023. The Author(s).
FAU - Madeira, Daniela
AU  - Madeira D
AUID- ORCID: 0000-0002-6027-5407
AD  - Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal.
AD  - Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Rua Larga, 
      Polo I FMUC, First Floor, 3004-504, Coimbra, Portugal.
FAU - Domingues, Joana
AU  - Domingues J
AD  - Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Rua Larga, 
      Polo I FMUC, First Floor, 3004-504, Coimbra, Portugal.
FAU - Lopes, Catia R
AU  - Lopes CR
AD  - Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal.
AD  - Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Rua Larga, 
      Polo I FMUC, First Floor, 3004-504, Coimbra, Portugal.
FAU - Canas, Paula M
AU  - Canas PM
AD  - Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Rua Larga, 
      Polo I FMUC, First Floor, 3004-504, Coimbra, Portugal.
FAU - Cunha, Rodrigo A
AU  - Cunha RA
AUID- ORCID: 0000-0003-2550-6422
AD  - Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal.
AD  - Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Rua Larga, 
      Polo I FMUC, First Floor, 3004-504, Coimbra, Portugal.
FAU - Agostinho, Paula
AU  - Agostinho P
AUID- ORCID: 0000-0001-5523-4945
AD  - Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal. 
      pagostinho@fmed.uc.pt.
AD  - Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Rua Larga, 
      Polo I FMUC, First Floor, 3004-504, Coimbra, Portugal. pagostinho@fmed.uc.pt.
LA  - eng
GR  - HP17/00523/'la Caixa' Foundation/
GR  - CENTRO-01-0145-FEDER-000008:BrainHealth 2020/Programa Operacional Regional do 
      Centro/
GR  - CENTRO-01-0246-FEDER-000010/Programa Operacional Regional do Centro/
GR  - PTDC/MED-NEU/31274/2017/Fundacao para a Ciencia e a Tecnologia/
GR  - UIDB/04539/2020/Fundacao para a Ciencia e a Tecnologia/
GR  - SFRH/BD/139334/2018/Fundacao para a Ciencia e a Tecnologia/
GR  - 2021.06954.BD/Fundacao para a Ciencia e a Tecnologia/
PT  - Journal Article
DEP - 20231029
PL  - Switzerland
TA  - Cell Mol Life Sci
JT  - Cellular and molecular life sciences : CMLS
JID - 9705402
RN  - 0 (Connexin 43)
RN  - K72T3FS567 (Adenosine)
RN  - 0 (Amyloid beta-Peptides)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Alzheimer Disease/metabolism
MH  - Astrocytes/metabolism
MH  - Connexin 43/genetics/metabolism
MH  - Adenosine/metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Disease Models, Animal
PMC - PMC10613596
OTO - NOTNLM
OT  - Adenosine A2A receptors
OT  - Alzheimer's disease
OT  - Astrocytes
OT  - Connexin 43
OT  - Hemichannels
COIS- Rodrigo A. Cunha is a scientific advisor of the Institute for Scientific 
      Information on Coffee (ISIC).
EDAT- 2023/10/29 18:41
MHDA- 2023/10/31 06:42
PMCR- 2023/10/29
CRDT- 2023/10/29 15:08
PHST- 2023/06/09 00:00 [received]
PHST- 2023/09/26 00:00 [accepted]
PHST- 2023/09/07 00:00 [revised]
PHST- 2023/10/31 06:42 [medline]
PHST- 2023/10/29 18:41 [pubmed]
PHST- 2023/10/29 15:08 [entrez]
PHST- 2023/10/29 00:00 [pmc-release]
AID - 10.1007/s00018-023-04983-6 [pii]
AID - 4983 [pii]
AID - 10.1007/s00018-023-04983-6 [doi]
PST - epublish
SO  - Cell Mol Life Sci. 2023 Oct 29;80(11):340. doi: 10.1007/s00018-023-04983-6.