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Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model

Author

Listed:
  • Andrea Delekate

    (German Center for Neurodegenerative Diseases (DZNE))

  • Martina Füchtemeier

    (Charité—University Medicine Berlin
    German Center for Neurodegenerative Diseases (DZNE))

  • Toni Schumacher

    (German Center for Neurodegenerative Diseases (DZNE))

  • Cordula Ulbrich

    (German Center for Neurodegenerative Diseases (DZNE))

  • Marco Foddis

    (Charité—University Medicine Berlin)

  • Gabor C. Petzold

    (German Center for Neurodegenerative Diseases (DZNE)
    University Hospital Bonn)

Abstract

Astrocytic network alterations have been reported in Alzheimer’s disease (AD), but the underlying pathways have remained undefined. Here we measure astrocytic calcium, cerebral blood flow and amyloid-β plaques in vivo in a mouse model of AD using multiphoton microscopy. We find that astrocytic hyperactivity, consisting of single-cell transients and calcium waves, is most pronounced in reactive astrogliosis around plaques and is sometimes associated with local blood flow changes. We show that astroglial hyperactivity is reduced after P2 purinoreceptor blockade or nucleotide release through connexin hemichannels, but is augmented by increasing cortical ADP concentration. P2X receptor blockade has no effect, but inhibition of P2Y1 receptors, which are strongly expressed by reactive astrocytes surrounding plaques, completely normalizes astrocytic hyperactivity. Our data suggest that astroglial network dysfunction is mediated by purinergic signalling in reactive astrocytes, and that intervention aimed at P2Y1 receptors or hemichannel-mediated nucleotide release may help ameliorate network dysfunction in AD.

Suggested Citation

  • Andrea Delekate & Martina Füchtemeier & Toni Schumacher & Cordula Ulbrich & Marco Foddis & Gabor C. Petzold, 2014. "Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6422
    DOI: 10.1038/ncomms6422
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    Cited by:

    1. Michaela M. Novakovic & Kirill S. Korshunov & Rogan A. Grant & Megan E. Martin & Hiam A. Valencia & G. R. Scott Budinger & Jelena Radulovic & Murali Prakriya, 2023. "Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Eiji Shigetomi & Hideaki Suzuki & Yukiho J. Hirayama & Fumikazu Sano & Yuki Nagai & Kohei Yoshihara & Keisuke Koga & Toru Tateoka & Hideyuki Yoshioka & Youichi Shinozaki & Hiroyuki Kinouchi & Kenji F., 2024. "Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Annamaria Lia & Gabriele Sansevero & Angela Chiavegato & Miriana Sbrissa & Diana Pendin & Letizia Mariotti & Tullio Pozzan & Nicoletta Berardi & Giorgio Carmignoto & Cristina Fasolato & Micaela Zonta, 2023. "Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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