The Library
M1 muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease
Tools
Tools
Tools
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. and Tobin, Andrew B. (2022) M1 muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease. Science Signaling, 15 (760). eabm3720. doi:10.1126/scisignal.abm3720 ISSN 1937-9145.
|
PDF
WRAP-M1-muscarinic-receptor-activation-reduces-molecular-pathology-slows-22.pdf - Accepted Version - Requires a PDF viewer. Download (638Kb) | Preview |
Official URL: https://doi.org/10.1126/scisignal.abm3720
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 M 1 acetylcholine muscarinic receptor (M 1 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 1 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 1 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 1 receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein.
| Item Type: | Journal Article | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||||||||
| SWORD Depositor: | Library Publications Router | ||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Muscarinic receptors , Nervous system -- Degeneration , Nervous system -- Degeneration -- Molecular aspect | ||||||||||||||||||
| Journal or Publication Title: | Science Signaling | ||||||||||||||||||
| Publisher: | American Association for the Advancement of Science (AAAS) | ||||||||||||||||||
| ISSN: | 1937-9145 | ||||||||||||||||||
| Official Date: | 15 November 2022 | ||||||||||||||||||
| Dates: |
|
||||||||||||||||||
| Volume: | 15 | ||||||||||||||||||
| Number: | 760 | ||||||||||||||||||
| Article Number: | eabm3720 | ||||||||||||||||||
| DOI: | 10.1126/scisignal.abm3720 | ||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||
| Reuse Statement (publisher, data, author rights): | This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on 15(760) https://doi.org/10.1126/scisignal.abm3720 | ||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||
| Date of first compliant deposit: | 9 December 2022 | ||||||||||||||||||
| Date of first compliant Open Access: | 9 December 2022 | ||||||||||||||||||
| RIOXX Funder/Project Grant: |
|
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
Downloads
Downloads per month over past year
