M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

Bradley, S. J. et al. (2017) M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. Journal of Clinical Investigation, 127(2), pp. 487-499. (doi: 10.1172/JCI87526) (PMID:27991860) (PMCID:PMC5272187)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bourgognon, Dr Julie-Myrtille and Molloy, Mr Colin and Bradley, Dr Sophie and Tobin, Andrew
Authors: Bradley, S. J., Bourgognon, J.-M., Sanger, H. E., Verity, N., Mogg, A. J., White, D. J., Moreno, J. A., Butcher, A. J., Molloy, C., Macedo-Hatch, T., Edwards, J. M., Wess, J., Pawlak, R., Read, D. J., Sexton, P. M., Broad, L. M., Mallucci, G. R., Steinert, J. R., Christopoulos, A., Felder, C. C., and Tobin, A. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238
Published Online:19 December 2016
Copyright Holders:Copyright © 2016 Americal Society for Clinical Investigation
First Published:First published in Journal of Clinical Investigation 127(2):487-499
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
750161Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOME)201529/Z/16/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY