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.

Abstract

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.

Citation

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. https://doi.org/10.1126/scisignal.abm3720

• 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
• DOI: https://doi.org/10.1126/scisignal.abm3720
• Keywords: Cell Biology; Molecular Biology; Biochemistry
• Public URL: https://nottingham-repository.worktribe.com/output/13755301
• Publisher URL: https://www.science.org/doi/10.1126/scisignal.abm3720