{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:33:26Z","timestamp":1793090006561,"version":"4.5.0"},"reference-count":58,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"760","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2022,11,15]]},"abstract":"<jats:p>\n            Many dementias are propagated through the spread of \u201cprion-like\u201d misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer\u2019s disease (AD), for which no treatments are available to slow or stop progression. The M\n            <jats:sub>1<\/jats:sub>\n            acetylcholine muscarinic receptor (M\n            <jats:sub>1<\/jats:sub>\n            receptor) is abundant in the brain, and its activity promotes cognitive function in preclinical models and in patients with AD. Here, we investigated whether activation of the M\n            <jats:sub>1<\/jats:sub>\n            receptor might slow the progression of neurodegeneration associated with prion-like misfolded protein in a mouse model of prion disease. Proteomic and transcriptomic analysis of the hippocampus revealed that this model had a molecular profile that was similar to that of human neurodegenerative diseases, including AD. Chronic enhancement of the activity of the M\n            <jats:sub>1<\/jats:sub>\n            receptor with the positive allosteric modulator (PAM) VU0486846 reduced the abundance of prion-induced molecular markers of neuroinflammation and mitochondrial dysregulation in the hippocampus and normalized the abundance of those associated with neurotransmission, including synaptic and postsynaptic signaling components. PAM treatment of prion-infected mice prolonged survival and maintained cognitive function. Thus, allosteric activation of M\n            <jats:sub>1<\/jats:sub>\n            receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein.\n          <\/jats:p>","DOI":"10.1126\/scisignal.abm3720","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T18:58:19Z","timestamp":1668538699000},"source":"Crossref","is-referenced-by-count":18,"title":["M\n            <sub>1<\/sub>\n            muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7024-6450","authenticated-orcid":true,"given":"Louis","family":"Dwomoh","sequence":"first","affiliation":[{"name":"Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7004-0225","authenticated-orcid":true,"given":"Mario","family":"Rossi","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Scarpa","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham","family":"Khajehali","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia."},{"name":"Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3010, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7179-7721","authenticated-orcid":true,"given":"Colin","family":"Molloy","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Herzyk","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2252-1689","authenticated-orcid":true,"given":"Shailesh N.","family":"Mistry","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5182-3643","authenticated-orcid":true,"given":"Andrew R.","family":"Bottrill","sequence":"additional","affiliation":[{"name":"Research Technology Platforms, University of Warwick, School of Life Sciences, Coventry CV4 7AL, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-2473","authenticated-orcid":true,"given":"Patrick M.","family":"Sexton","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia."},{"name":"Australian Research Council Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4442-3294","authenticated-orcid":true,"given":"Arthur","family":"Christopoulos","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia."},{"name":"Australian Research Council Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2363-0323","authenticated-orcid":true,"given":"P. Jeffrey","family":"Conn","sequence":"additional","affiliation":[{"name":"Warren Centre for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0168-1445","authenticated-orcid":true,"given":"Craig W.","family":"Lindsley","sequence":"additional","affiliation":[{"name":"Warren Centre for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-4090","authenticated-orcid":true,"given":"Sophie J.","family":"Bradley","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1807-3123","authenticated-orcid":true,"given":"Andrew B.","family":"Tobin","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2010.04.003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R114.568477"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R114.583492"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121898"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.4161\/pri.3.4.9981"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.281"},{"key":"e_1_3_3_8_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrd.2017.43","article-title":"BACE inhibitor bust in Alzheimer trial","volume":"16","author":"Mullard A.","year":"2017","unstructured":"A.\u00a0Mullard,BACE inhibitor bust in Alzheimer trial. 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