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.

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M1 receptors

“…Our data showing that the pharmacological profile of SPP1 is conserved in AD cortical tissue is consistent with other data indicating that postsynaptic M 1 receptors are still present in such samples, and function is retained (Overk et al ., ; Nathan et al ., ; Bradley et al ., ). These data confirm therefore that targeting these receptors in AD is a valid approach to increasing cholinergic signalling.…”

“…Shirey et al, 2009;Uslaner et al, 2013;Lange et al, 2015;Puri et al, 2015;Vardigan et al, 2015;Butcher et al, 2016;Dennis et al, 2016;Betterton et al, 2017). A high level of expression of M 1 receptors in cortex and hippocampus is conserved across species, including in brains from human AD patients (Overk et al, 2010;Bradley et al, 2017).…”

M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluAl subunit

“…Significant reduction of M1 mAChRs is consistently manifested in the postmortem brains of patients with schizophrenia (6,11). Consistent with these findings, knockout mutation or pharmacologic manipulation of M1 mAChRs impairs learning and memory (8,12). Activation or positive allosteric modulation of M1 mAChRs improves cognitive performance and ameliorates memory deficits in animal models (13)(14)(15).…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Current evidence suggests that the M 1 receptor plays a vital role in mediating cholinergic pro-cognitive effects. In addition to the M 1 PAM efficacy observed in healthy rodents and schizophrenia models discussed above, M 1 PAMs have pro-cognitive effects in numerous rodent models of AD (Puri et al, 2015; Shirey et al, 2009), and can reverse cognitive deficits and prolong survival in a mouse model of prion disease that shows AD-like pathology (Bradley et al, 2016). As discussed above in the context of mGlu 2 PAMs for schizophrenia, it is possible that careful patient stratification will be critical for evaluating the potential efficacy of M 1 PAMs in patient populations.…”