M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.
M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.
复制标题
M1毒蕈碱变构调节剂慢速神经变性并恢复记忆丧失。
DOI：
10.1172/jci87526
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发表时间：
2017-02-01
期刊：
影响因子：
--
通讯作者：
Tobin AB
中科院分区：
文献类型：
--
作者：
Bradley SJ;Bourgognon JM;Sanger HE;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
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.
