dc.contributor.author | Bradley, SJ | |
dc.contributor.author | Bourgognon, J-M | |
dc.contributor.author | Sanger, HE | |
dc.contributor.author | Verity, N | |
dc.contributor.author | Mogg, AJ | |
dc.contributor.author | White, DJ | |
dc.contributor.author | Butcher, AJ | |
dc.contributor.author | Moreno, JA | |
dc.contributor.author | Molloy, C | |
dc.contributor.author | Macedo-Hatch, T | |
dc.contributor.author | Edwards, JM | |
dc.contributor.author | Wess, J | |
dc.contributor.author | Pawlak, R | |
dc.contributor.author | Read, DJ | |
dc.contributor.author | Sexton, PM | |
dc.contributor.author | Broad, LM | |
dc.contributor.author | Steinert, JR | |
dc.contributor.author | Mallucci, GR | |
dc.contributor.author | Christopoulos, A | |
dc.contributor.author | Felder, CC | |
dc.contributor.author | Tobin, AB | |
dc.date.accessioned | 2018-06-08T14:24:36Z | |
dc.date.issued | 2016-12-19 | |
dc.description.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. | en_GB |
dc.description.sponsorship | ABT, AC, and PMS received funding from a Wellcome Trust Collaborative
Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were
funded through a Medical Research Council programme leader
grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and
HES were funded by the Eli Lilly Company. JMB received funding
through a Lilly Research Award Program (LRAP) grant (Eli
Lilly). RP received funding from the Marie Curie grant “Extrabrain”
(European Commission). AC is a senior principal research
fellow and PMS a principal research fellow of the National Health
and Medical Research Council of Australia. Tissue samples were
from Randy Woltjer at the Oregon Alzheimer’s Disease Center.
The Oregon Alzheimer’s Disease Center is supported by NIH grant P30AG008017. | en_GB |
dc.identifier.citation | Vol. 127 (2), pp. 487-499 | en_GB |
dc.identifier.doi | 10.1172/JCI87526 | |
dc.identifier.uri | http://hdl.handle.net/10871/33127 | |
dc.language.iso | en | en_GB |
dc.publisher | American Society for Clinical Investigation | en_GB |
dc.rights | Open access. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | en_GB |
dc.subject | memory loss | en_GB |
dc.subject | M1 muscarinic acetylcholine receptor | en_GB |
dc.subject | M1 mACh | en_GB |
dc.title | M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-06-08T14:24:36Z | |
dc.identifier.issn | 0021-9738 | |
dc.description | This is the final version of the article. Available from American Society for Clinical Investigation via the DOI in this record. | en_GB |
dc.identifier.journal | Journal of Clinical Investigation | en_GB |