title: Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model.
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.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Delekate
authors.affiliation: 1] Department of Experimental Neurology, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Füchtemeier
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Schumacher
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Ulbrich
authors.affiliation: Department of Experimental Neurology, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Foddis
authors.affiliation: 1] German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany [2] Department of Neurology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
authors.forename: Gabor C
authors.initials: GC
authors.lastname: Petzold
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D020013:Calcium Signaling; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D058225:Plaque, Amyloid / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C546383:P2ry1 protein, mouse; D058472:Receptors, Purinergic P2Y1; D000255:Adenosine Triphosphate