M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

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 & 1 others Andrew B. Tobin

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)487-499
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number2
DOIs
Publication statusPublished - 1 Feb 2017

Cite this

Bradley, S. J., Bourgognon, J. M., Sanger, H. E., Verity, N., Mogg, A. J., White, D. J., ... Tobin, A. B. (2017). M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. Journal of Clinical Investigation, 127(2), 487-499. https://doi.org/10.1172/JCI87526
Bradley, Sophie J. ; Bourgognon, Julie Myrtille ; Sanger, Helen E. ; Verity, Nicholas ; Mogg, Adrian J. ; White, David J. ; Butcher, Adrian J. ; Moreno, Julie A. ; Molloy, Colin ; Macedo-Hatch, Timothy ; Edwards, Jennifer M. ; Wess, Jurgen ; Pawlak, Robert ; Read, David J. ; Sexton, Patrick M. ; Broad, Lisa M. ; Steinert, Joern R. ; Mallucci, Giovanna R. ; Christopoulos, Arthur ; Felder, Christian C. ; Tobin, Andrew B. / M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 2. pp. 487-499.
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title = "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.",
author = "Bradley, {Sophie J.} and Bourgognon, {Julie Myrtille} and Sanger, {Helen E.} and Nicholas Verity and Mogg, {Adrian J.} and White, {David J.} and Butcher, {Adrian J.} and Moreno, {Julie A.} and Colin Molloy and Timothy Macedo-Hatch and Edwards, {Jennifer M.} and Jurgen Wess and Robert Pawlak and Read, {David J.} and Sexton, {Patrick M.} and Broad, {Lisa M.} and Steinert, {Joern R.} and Mallucci, {Giovanna R.} and Arthur Christopoulos and Felder, {Christian C.} and Tobin, {Andrew B.}",
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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 2017, 'M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss' Journal of Clinical Investigation, vol. 127, no. 2, pp. 487-499. https://doi.org/10.1172/JCI87526

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. / Bradley, Sophie J.; Bourgognon, Julie Myrtille; Sanger, Helen E.; Verity, Nicholas; Mogg, Adrian J.; White, David J.; Butcher, Adrian J.; Moreno, Julie A.; Molloy, Colin; Macedo-Hatch, Timothy; Edwards, Jennifer M.; Wess, Jurgen; Pawlak, Robert; Read, David J.; Sexton, Patrick M.; Broad, Lisa M.; Steinert, Joern R.; Mallucci, Giovanna R.; Christopoulos, Arthur; Felder, Christian C.; Tobin, Andrew B.

In: Journal of Clinical Investigation, Vol. 127, No. 2, 01.02.2017, p. 487-499.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bradley, Sophie J.

AU - Bourgognon, Julie Myrtille

AU - Sanger, Helen E.

AU - Verity, Nicholas

AU - Mogg, Adrian J.

AU - White, David J.

AU - Butcher, Adrian J.

AU - Moreno, Julie A.

AU - Molloy, Colin

AU - Macedo-Hatch, Timothy

AU - Edwards, Jennifer M.

AU - Wess, Jurgen

AU - Pawlak, Robert

AU - Read, David J.

AU - Sexton, Patrick M.

AU - Broad, Lisa M.

AU - Steinert, Joern R.

AU - Mallucci, Giovanna R.

AU - Christopoulos, Arthur

AU - Felder, Christian C.

AU - Tobin, Andrew B.

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N2 - 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.

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Bradley SJ, Bourgognon JM, Sanger HE, Verity N, Mogg AJ, White DJ et al. M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. Journal of Clinical Investigation. 2017 Feb 1;127(2):487-499. https://doi.org/10.1172/JCI87526