P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model
Open accessAbstract
Astrocytic hyperactivity is an important contributor to neuronal-glial network dysfunction in Alzheimer’s disease (AD). We have previously shown that astrocyte hyperactivity is mediated by signaling through the P2Y1 purinoreceptor (P2Y1R) pathway. Using the APPPS1 mouse model of AD, we here find that chronic intracerebroventricular infusion of P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, as measured by in vivo two-photon microscopy, augments structural synaptic integrity, and preserves hippocampal long-term potentiation. These effects occur independently from β-amyloid metabolism or plaque burden but are associated with a higher morphological complexity of periplaque reactive astrocytes, as well as reduced dystrophic neurite burden and greater plaque compaction. Importantly, APPPS1 mice chronically treated with P2Y1R antagonists, as well as APPPS1 mice carrying an astrocyte-specific genetic deletion (Ip3r2−/−) of signaling pathways downstream of P2Y1R activation, are protected from the decline of spatial learning and memory. In summary, our study establishes the restoration of network homoeostasis by P2Y1R inhibition as a novel treatment target in AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Interventional strategies such as classical pharmacology, genetic manipulation, and biomaterials are available tools to modify pathological signaling in reactive astrocytes for therapeutic purposes.
“Finally, interventional strategies such as classical pharmacology56,98, genetic manipulation42,56, and biomaterials99 are available tools to modify pathological signaling in reactive astrocytes for therapeutic purposes.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [56]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226 · see citing works
Self-citationGliotransmitters Travel in Time and Space
Araque, A., Carmignoto, G., Haydon, P. G., Oliet, S. H. R., Robitaille, R., & Volterra, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.007 · Cited by 1,308 · see citing works
Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice
Shi, Q., Chowdhury, S., Ma, R., Le, K. X., Hong, S., Caldarone, B. J., Stevens, B., & Lemere, C. A. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6295 · Cited by 593 · cited 2× · see citing works
“…chronic MRS2179 treatment on hippocampal CA1 synapses, we performed high-resolution confocal microscopy analysis of the colabeled pre- and postsynaptic markers synaptophysin and Homer1—i.e., synaptic puncta (Shi et al., 2017)—in brain sections from APP PS1 mice and age-matched WT littermates (Fig.”
BackgroundMethodDelekate, A., Füchtemeier, M., Schumacher, T., Ulbrich, C., Foddis, M., & Petzold, G. C. (2014) · Nature Communications · doi:10.1038/ncomms6422 · Cited by 332 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 30
- Boyer J.L., Mohanram A., Camaioni E., Jacobson K.A., and Harden T.K. 1998 Competitive and selective antagonism of P2Y1 receptors by N6-methyl 2′-deoxyadenosine 3′,5′-bisphosphate. Br. J. Pharmacol. 124: 1– 3. 10.1038/sj.bjp.0701837 9630335 PMC1565379 · DOI
- Busche M.A., Eichhoff G., Adelsberger H., Abramowski D., Wiederhold K.-H., Haass C., Staufenbiel M., Konnerth A., and Garaschuk O. 2008 Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science. 321: 1686– 1689. 10.1126/science.1162844 18802001 · DOI · Paper page
- Chhatriwala M., Ravi R.G., Patel R.I., Boyer J.L., Jacobson K.A., and Harden T.K. 2004 Induction of novel agonist selectivity for the ADP-activated P2Y1 receptor versus the ADP-activated P2Y12 and P2Y13 receptors by conformational constraint of an ADP analog. J. Pharmacol. Exp. Ther. 311: 1038– 1043. 10.1124/jpet.104.068650 15345752 PMC3459333 · DOI
- Condello C., Schain A., and Grutzendler J. 2011 Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Sci. Rep. 1: 19 10.1038/srep00019 22355538 PMC3216507 · DOI
- Condello C., Yuan P., Schain A., and Grutzendler J. 2015 Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6: 6176 10.1038/ncomms7176 25630253 PMC4311408 · DOI · Paper page
- Domercq M., Brambilla L., Pilati E., Marchaland J., Volterra A., and Bezzi P. 2006 P2Y1 receptor-evoked glutamate exocytosis from astrocytes: Control by tumor necrosis factor-alpha and prostaglandins. J. Biol. Chem. 281: 30684– 30696. 10.1074/jbc.M606429200 16882655 · DOI
- Dzyubenko E., Rozenberg A., Hermann D.M., and Faissner A. 2016 Colocalization of synapse marker proteins evaluated by STED-microscopy reveals patterns of neuronal synapse distribution in vitro. J. Neurosci. Methods. 273: 149– 159. 10.1016/j.jneumeth.2016.09.001 27615741 · DOI
- Franke H., Verkhratsky A., Burnstock G., and Illes P. 2012 Pathophysiology of astroglial purinergic signalling. Purinergic Signal. 8: 629– 657. 10.1007/s11302-012-9300-0 22544529 PMC3360100 · DOI
- Gengler S., Hamilton A., and Hölscher C. 2010 Synaptic plasticity in the hippocampus of a APP/PS1 mouse model of Alzheimer’s disease is impaired in old but not young mice. PLoS One. 5: e9764 10.1371/journal.pone.0009764 20339537 PMC2842299 · DOI
- Jourdain P., Bergersen L.H., Bhaukaurally K., Bezzi P., Santello M., Domercq M., Matute C., Tonello F., Gundersen V., and Volterra A. 2007 Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10: 331– 339. 10.1038/nn1849 17310248 · DOI
- Kuchibhotla K.V., Goldman S.T., Lattarulo C.R., Wu H.-Y., Hyman B.T., and Bacskai B.J. 2008 Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron. 59: 214– 225. 10.1016/j.neuron.2008.06.008 18667150 PMC2578820 · DOI · Paper page
- Kuchibhotla K.V., Lattarulo C.R., Hyman B.T., and Bacskai B.J. 2009 Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science. 323: 1211– 1215. 10.1126/science.1169096 19251629 PMC2884172 · DOI · Paper page
- Li X., Zima A.V., Sheikh F., Blatter L.A., and Chen J. 2005 Endothelin-1-induced arrhythmogenic Ca2+ signaling is abolished in atrial myocytes of inositol-1,4,5-trisphosphate (IP3)-receptor type 2-deficient mice. Circ. Res. 96: 1274– 1281. 10.1161/01.RES.0000172556.05576.4c 15933266 · DOI
- Minge D., Senkov O., Kaushik R., Herde M.K., Tikhobrazova O., Wulff A.B., Mironov A., van Kuppevelt T.H., Oosterhof A., Kochlamazashvili G., 2017 Heparan sulfates support pyramidal cell excitability, synaptic plasticity, and context discrimination. Cereb. Cortex. 27: 903– 918. 10.1093/cercor/bhx003 28119345 PMC5390399 · DOI
- Ortinski P.I., Dong J., Mungenast A., Yue C., Takano H., Watson D.J., Haydon P.G., and Coulter D.A. 2010 Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci. 13: 584– 591. 10.1038/nn.2535 20418874 PMC3225960 · DOI · Paper page
- Palop J.J., and Mucke L. 2016 Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17: 777– 792. 10.1038/nrn.2016.141 27829687 PMC8162106 · DOI · Paper page
- Palop J.J., Chin J., Roberson E.D., Wang J., Thwin M.T., Bien-Ly N., Yoo J., Ho K.O., Yu G.-Q., Kreitzer A., 2007 Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron. 55: 697– 711. 10.1016/j.neuron.2007.07.025 17785178 PMC8055171 · DOI · Paper page
- Petzold G.C., and Murthy V.N. 2011 Role of astrocytes in neurovascular coupling. Neuron. 71: 782– 797. 10.1016/j.neuron.2011.08.009 21903073 · DOI · Paper page
- Pompl P.N., Mullan M.J., Bjugstad K., and Arendash G.W. 1999 Adaptation of the circular platform spatial memory task for mice: Use in detecting cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer’s disease. J. Neurosci. Methods. 87: 87– 95. 10.1016/S0165-0270(98)00169-1 10065997 · DOI
- Radde R., Bolmont T., Kaeser S.A., Coomaraswamy J., Lindau D., Stoltze L., Calhoun M.E., Jäggi F., Wolburg H., Gengler S., 2006 Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7: 940– 946. 10.1038/sj.embor.7400784 16906128 PMC1559665 · DOI · Paper page
- Reiman E.M., Quiroz Y.T., Fleisher A.S., Chen K., Velez-Pardo C., Jimenez-Del-Rio M., Fagan A.M., Shah A.R., Alvarez S., Arbelaez A., 2012 Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: A case-control study. Lancet Neurol. 11: 1048– 1056. 10.1016/S1474-4422(12)70228-4 23137948 PMC4181671 · DOI · Paper page
- Robel S., and Sontheimer H. 2016 Glia as drivers of abnormal neuronal activity. Nat. Neurosci. 19: 28– 33. 10.1038/nn.4184 26713746 PMC4966160 · DOI
- Sanchez P.E., Zhu L., Verret L., Vossel K.A., Orr A.G., Cirrito J.R., Devidze N., Ho K., Yu G.-Q., Palop J.J., and Mucke L. 2012 Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc. Natl. Acad. Sci. USA. 109: E2895– E2903. 10.1073/pnas.1121081109 22869752 PMC3479491 · DOI · Paper page
- Schmid L.C., Mittag M., Poll S., Steffen J., Wagner J., Geis H.-R., Schwarz I., Schmidt B., Schwarz M.K., Remy S., and Fuhrmann M. 2016 Dysfunction of somatostatin-positive interneurons associated with memory deficits in an Alzheimer’s disease model. Neuron. 92: 114– 125. 10.1016/j.neuron.2016.08.034 27641495 · DOI
- Sharp A.H., Nucifora F.C. Jr., Blondel O., Sheppard C.A., Zhang C., Snyder S.H., Russell J.T., Ryugo D.K., and Ross C.A. 1999 Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain. J. Comp. Neurol. 406: 207– 220. 10.1002/(SICI)1096-9861(19990405)406:2<207::AID-CNE6>3.0.CO;2-7 10096607 · DOI
- Sperling R.A., Laviolette P.S., O’Keefe K., O’Brien J., Rentz D.M., Pihlajamaki M., Marshall G., Hyman B.T., Selkoe D.J., Hedden T., 2009 Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron. 63: 178– 188. 10.1016/j.neuron.2009.07.003 19640477 PMC2738994 · DOI · Paper page
- Thrane A.S., Rangroo Thrane V., Zeppenfeld D., Lou N., Xu Q., Nagelhus E.A., and Nedergaard M. 2012 General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex. Proc. Natl. Acad. Sci. USA. 109: 18974– 18979. 10.1073/pnas.1209448109 23112168 PMC3503159 · DOI
- Vossel K.A., Ranasinghe K.G., Beagle A.J., Mizuiri D., Honma S.M., Dowling A.F., Darwish S.M., Van Berlo V., Barnes D.E., Mantle M., 2016 Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann. Neurol. 80: 858– 870. 10.1002/ana.24794 27696483 PMC5177487 · DOI · Paper page
- Yuan P., Condello C., Keene C.D., Wang Y., Bird T.D., Paul S.M., Luo W., Colonna M., Baddeley D., and Grutzendler J. 2016 TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 90: 724– 739. 10.1016/j.neuron.2016.05.003 27196974 PMC4898967 · DOI · Paper page
- Zhang D., Gao Z.-G., Zhang K., Kiselev E., Crane S., Wang J., Paoletta S., Yi C., Ma L., Zhang W., 2015 Two disparate ligand-binding sites in the human P2Y1 receptor. Nature. 520: 317– 321. 10.1038/nature14287 25822790 PMC4408927 · DOI
Cited by
Sorted by citations
Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,533 · see citing works
Self-citationAstrocyte function from information processing to cognition and cognitive impairment
Santello, M., Toni, N., & Volterra, A. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0325-8 · Cited by 737 · see citing works
Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders
Brandebura, A. N., Paumier, A., Onur, T. S., & Allen, N. J. (2023) · Nature Reviews Neuroscience · doi:10.1038/s41583-022-00641-1 · Cited by 427 · see citing works
Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model
Reichenbach, N., Delekate, A., Plescher, M., Schmitt, F., Krauss, S., Blank, N., Halle, A., & Petzold, G. C. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809665 · Cited by 343 · see citing works
Self-citationThe identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer’s Disease
Franco-Bocanegra, D. K., McAuley, C., Nicoll, J. A. R., & Boche, D. (2019) · Cells · doi:10.3390/cells8060639 · Cited by 147 · see citing works
- Authors
- Reichenbach, N., Delekate, A., Breithausen, B., Keppler, K., Poll, S., Schulte, T., Peter, J., Plescher, M., Hansen, J. N., Blank, N., Keller, A., Fuhrmann, M., Henneberger, C., Halle, A., & Petzold, G. C.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- University Hospital Bonn (DE)
- German Center for Neurodegenerative Diseases, Bonn, Germany 1
- Corresponding author
- Petzold, Gabor C.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2018-05-03
- Volume
- 215
- Issue
- 6
- Pages
- 1649-1663
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5987918
- OpenAlex
- W2802704558
- Cited by
- 131
- References
- 5
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 13 · 2023: 17 · 2022: 23 · 2021: 16 · 2020: 19 · 2019: 10 · 2018: 6
- FWCI
- 8.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion, other-oa)
- DZNE Pub
- Funders
- European Union (EU) Joint Program
- Neurodegenerative Disease Research program
- Horizon 2020 Framework Programme (643417/DACAPO-AD)
- Alzheimer Forschung Initiative
- German Center for Neurodegenerative Diseases
- German Research Foundation
- Cluster of Excellence ImmunoSensation (EXC 1023)
- North Rhine-Westphalia Rückkehrerprogramm
- DFG (SFB1089)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, P2Y1 receptor, purinergic signaling, APP/PS1 mice, intracerebroventricular infusion, synaptic integrity, long-term potentiation, amyloid plaques, dystrophic neurites, spatial learning and memory, IP3R2, cognitive impairment
- MeSH terms
- Adenosine Diphosphate, Alzheimer Disease, Animals, Astrocytes, Cognition, Disease Models, Animal, Hippocampus, Humans, Memory, Mice, Transgenic, Nerve Net, Neurons, Synapses, Signal Transduction, Plaque, Amyloid, Receptors, Purinergic P2Y1, Purinergic P2Y Receptor Antagonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
