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 4

The orthosteric mAChR agonist xanomeline restores the learning and memory deficit in prion-infected mice.

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The orthosteric mAChR agonist xanomeline restores the learning and memor...
(A) Chemical structure of xanomeline. (B) [35S]-GTPγS binding to membranes prepared from control or prion-infected mice (9–10 w.p.i.) in response to xanomeline are expressed as a percentage of the maximal response observed with oxotremorine-M. Mean pEC50 for xanomeline on control membranes = 7.67 ± 0.04, prion 9 w.p.i. membranes = 7.73 ± 0.06, and prion 10 w.p.i. membranes = 7.65 ± 0.13. n = 3. (C) [35S]-GTPγS binding to membranes prepared from the frontal cortex of control or AD patients in response to xanomeline. Data are expressed as the percentage of the maximal [35S]-GTPγS binding stimulated by oxotremorine-M. Mean pEC50 values of 8.14 ± 0.28 (control) and 7.34 ± 0.36 (AD). n = 3. (D) Fear-conditioning response of control and prion-infected mice following administration of vehicle or xanomeline (5 mg/kg) 30 minutes prior to training and retrieval. n ≥ 6. Statistical analysis by 1 -way ANOVA. **P < 0.01. (E) Burrowing response of control and prion-infected mice following administration of vehicle or xanomeline (5 mg/kg) 30 minutes before each burrowing session (from 7 w.p.i.). (F, G, and H ) AUC of AMPA receptor–mediated currents before and after treatment with xanomeline in control (F, n = 10) and prion-infected (G and H, n = 12) hippocampi. *P < 0.05, paired Student’s t test. Also shown in G are representative traces of paired whole cell CA1 glutamatergic current recordings in vehicle-treated (black) and xanomeline-treated (100 nM) (red) hippocampal slices of a prion-infected mouse. (I) Western blot of hippocampal lysates prepared from prion-infected mice treated with vehicle or xanomeline (Xan, 5 mg/kg) and probed with an antibody that detects phospho-S880 of GluR2 AMPA receptor subunits (total GluR2 was used as a loading control). (J) Quantification of I. n = 3. **P < 0.01, paired Student’s t test. Data are shown as mean ± SEM.