期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 2, 页码 487-499出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI87526
关键词
-
资金
- Wellcome Trust Collaborative Award [201529/Z/16/Z]
- Medical Research Council
- Eli Lilly Company
- Lilly Research Award Program (LRAP) grant (Eli Lilly)
- NIH [P30AG008017]
- Marie Curie grant Extrabrain (European Commission)
- MRC [MC_UP_A600_1110, MC_U132692719, MR/P019366/1, MC_U132681855] Funding Source: UKRI
- Medical Research Council [MC_U132692719, MC_U132681855, 1241997] Funding Source: researchfish
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据