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M1 muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease

Dwomoh, Louis; Rossi, Mario; Scarpa, Miriam; Khajehali, Elham; Molloy, Colin; Herzyk, Pawel; Mistry, Shailesh N.; Bottrill, Andrew R.; Sexton, Patrick M.; Christopoulos, Arthur; Conn, Jeffrey; Lindsley, Craig W.; Bradley, Sophie J.; Tobin, Andrew B.


Louis Dwomoh

Mario Rossi

Miriam Scarpa

Elham Khajehali

Colin Molloy

Pawel Herzyk

Andrew R. Bottrill

Patrick M. Sexton

Arthur Christopoulos

Jeffrey Conn

Craig W. Lindsley

Sophie J. Bradley

Andrew B. Tobin


Many dementias are propagated through the spread of “prion-like” misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer’s disease (AD), for which no treatments are available to slow or stop progression. The M1 acetylcholine muscarinic receptor (M1 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 M1 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 M1 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 M1 receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein.


Dwomoh, L., Rossi, M., Scarpa, M., Khajehali, E., Molloy, C., Herzyk, P., …Tobin, A. B. (2022). M1 muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease. Science Signaling, 15(760), 00.

Journal Article Type Article
Acceptance Date Oct 19, 2022
Online Publication Date Nov 15, 2022
Publication Date Nov 15, 2022
Deposit Date Nov 18, 2022
Publicly Available Date Nov 25, 2022
Journal Science Signaling
Print ISSN 1945-0877
Electronic ISSN 1937-9145
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 15
Issue 760
Article Number 00
Pages 00
Keywords Cell Biology; Molecular Biology; Biochemistry
Public URL
Publisher URL


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