M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
Bradley, SJ; Bourgognon, J-M; Sanger, HE; et al.Verity, N; Mogg, AJ; White, DJ; Butcher, AJ; Moreno, JA; Molloy, C; Macedo-Hatch, T; Edwards, JM; Wess, J; Pawlak, R; Read, DJ; Sexton, PM; Broad, LM; Steinert, JR; Mallucci, GR; Christopoulos, A; Felder, CC; Tobin, AB
Date: 19 December 2016
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Publisher DOI
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 ...
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.
Institute of Biomedical & Clinical Science
Collections of Former Colleges
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