M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
Sophie J. Bradley, … , Christian C. Felder, Andrew B. Tobin
Sophie J. Bradley, … , Christian C. Felder, Andrew B. Tobin
Published December 19, 2016
Citation Information: J Clin Invest. 2017;127(2):487-499. https://doi.org/10.1172/JCI87526.
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Research Article Neuroscience

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

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

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Figure 5

PAMs of the M1 mAChR rescue the fear-conditioning learning and memory deficit in prion-infected mice.

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PAMs of the M1 mAChR rescue the fear-conditioning learning and memory de...
(A) Schematic summarizing the 3 possible effects of an allosteric modulator, namely, modulation of orthosteric ligand affinity, signaling efficacy, and/or direct activation. (B) BQCA (inset; chemical structure of BQCA) causes equivalent leftward shifts (black arrow) of the oxotremorine-M (Oxo-M) [35S]-GTPγS-assay concentration-response curve and displays intrinsic activity (red arrow) in hippocampal membranes derived from control and prion-infected mice (9 and 10 w.p.i.). Data are shown as mean ± SEM. n = 3. (C) Acetylcholine-stimulated [35S]-GTPγS binding to membranes prepared from the frontal cortex of control or AD patients in the absence and presence of BQCA (3 μM). Data are expressed as the percentage of the maximal [35S]-GTPγS binding stimulated by oxotremorine-M. Mean ± SEM. n = 3. (D) Fear-conditioning response of control and prion-infected mice following administration of vehicle or BQCA (15 mg/kg) 30 minutes prior to training. Mean ± SEM. n = 6–18. *P < 0.05; ***P < 0.001, 1-way ANOVA. (E) Radioligand competition binding between [3H]-NMS (~0.3 nM) and increasing concentrations of BQCA or BQZ-12 (inset, chemical structure of BQZ-12) in hippocampal membranes from control and prion-infected mice (9 and 10 w.p.i.). n = 3–4. The affinities (pKi) of BQCA and BQZ-12 at hippocampal membranes from prion-diseased mice (10 w.p.i.) were 6.15 ± 0.08 and 4.25 ± 0.12, respectively. Data are shown as mean ± SEM. n = 3. (F) Fear-conditioning response of control and prion-infected mice following administration of vehicle or BQZ-12 (1.5 mg/kg) 30 minutes prior to training. Data are shown as mean ± SEM. n = 12–19. *P < 0.05; ***P < 0.001, 1-way ANOVA.