Memory loss and other cognitive symptoms of Alzheimer’s disease are attributed, in part, to the degeneration of acetylcholine-producing neurons. Acetylcholinesterase inhibitors are a common treatment for patients with Alzheimer’s; however, in spite of their clinical benefits, these non-selective medications are also associated with numerous adverse effects. Work led by Andrew Tobin at the University of Leicester tested two drugs that specifically target the M1 muscarinic acetylcholine receptor in a mouse model of prion disease and discovered that the treatments had promising effects in reversing cognitive decline. The mouse model showed many hallmarks of human Alzheimer’s disease, including memory deficits and progressive hippocampal neuron degeneration. Treatment with the M1-selective medications reversed memory deficits and profoundly extended the lifespan of the diseased mice. These findings support the concept that more selective drugs can be effective in treating the cognitive symptoms of neurodegenerative disease.
The above image illustrates dying neurons (pink) in the hippocampus of mice with prion disease.
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.
Sophie J. Bradley, Julie-Myrtille Bourgognon, Helen E. Sanger, Nicholas Verity, Adrian J. Mogg, David J. White, Adrian J. Butcher, Julie A. Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M. Edwards, Jurgen Wess, Robert Pawlak, David J. Read, Patrick M. Sexton, Lisa M. Broad, Joern R. Steinert, Giovanna R. Mallucci, Arthur Christopoulos, Christian C. Felder, Andrew B. Tobin