Skip to main content

Research Repository

Advanced Search

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

Bradley, Sophie J.; Bourgognon, Julie-Myrtille; Sanger, Helen E.; Verity, Nicholas; Mogg, Adrian J.; White, David J.; Molloy, Colin; Butcher, Adrian J.; Moreno, Julie A.; Macedo-Hatch, Timothy; Edwards, Jennifer M.; Wess, Jurgen; Pawlak, Robert; Read, David J.; Sexton, Patrick M.; Broad, Lisa M.; Steinert, Joern R.; Mallucci, Giovanna R.; Christopoulos, Arthur; Felder, Christian C.; Tobin, Andrew B.

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss Thumbnail


Sophie J. Bradley

Julie-Myrtille Bourgognon

Helen E. Sanger

Nicholas Verity

Adrian J. Mogg

David J. White

Colin Molloy

Adrian J. Butcher

Julie A. Moreno

Timothy Macedo-Hatch

Jennifer M. Edwards

Jurgen Wess

Robert Pawlak

David J. Read

Patrick M. Sexton

Lisa M. Broad

Giovanna R. Mallucci

Arthur Christopoulos

Christian C. Felder

Andrew B. Tobin


The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.


Bradley, S. J., Bourgognon, J., Sanger, H. E., Verity, N., Mogg, A. J., White, D. J., …Tobin, A. B. (2017). M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. Journal of Clinical Investigation, 127(2), 487-499.

Journal Article Type Article
Acceptance Date Nov 3, 2016
Online Publication Date Dec 19, 2016
Publication Date 2017-02
Deposit Date Jun 17, 2020
Publicly Available Date Jun 22, 2020
Journal Journal of Clinical Investigation
Print ISSN 0021-9738
Electronic ISSN 1558-8238
Publisher American Society for Clinical Investigation
Peer Reviewed Peer Reviewed
Volume 127
Issue 2
Pages 487-499
Public URL
Publisher URL


You might also like

Downloadable Citations