title: M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.
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.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Bradley
authors.forename: Julie-Myrtille
authors.initials: JM
authors.lastname: Bourgognon
authors.forename: Helen E
authors.initials: HE
authors.lastname: Sanger
authors.forename: Nicholas
authors.initials: N
authors.lastname: Verity
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mogg
authors.forename: David J
authors.initials: DJ
authors.lastname: White
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Butcher
authors.forename: Julie A
authors.initials: JA
authors.lastname: Moreno
authors.forename: Colin
authors.initials: C
authors.lastname: Molloy
authors.forename: Timothy
authors.initials: T
authors.lastname: Macedo-Hatch
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Edwards
authors.forename: Jurgen
authors.initials: J
authors.lastname: Wess
authors.forename: Robert
authors.initials: R
authors.lastname: Pawlak
authors.forename: David J
authors.initials: DJ
authors.lastname: Read
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Broad
authors.forename: Joern R
authors.initials: JR
authors.lastname: Steinert
authors.forename: Giovanna R
authors.initials: GR
authors.lastname: Mallucci
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Tobin
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D017096:Prion Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011804:Quinolines / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C583161:1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D011804:Quinolines; D043643:Receptor, Muscarinic M1