The paper by Davis et al. adds further support to the major and pivotal role of the M1 muscarinic receptor (M1 AChR) in AD pathology and possible treatment with selective M1 agonists. It adds indirect support to our earlier findings that M1 agonists such as AF267B could be a highly promising and causal treatment in AD (Caccamo et al., 2006; Fisher, 2008). While this paper represents a major step towards our understanding in M1 AChR-mediated APP processing, I would like to address the following points:

1. Carbachol in the M1 knockout mice increased Aβ production, probably via stimulation of other non-M1 muscarinic receptor subtypes. It can be speculated that this is not due to its agonistic activity on M3 AChR or some nicotinic receptor subtypes. Furthermore, since it appears that mainly the activation of the M1 AChR is responsible for the decrease in Aβ production, while the M2 and M4 AChR may have an opposite effect, this may explain why treatment with cholinesterase inhibitors lack an effect on Aβ production in AD patients. Notably, such treatments increase synaptic ACh...  Read more

The paper by Davis et al. adds further support to the major and pivotal role of the M1 muscarinic receptor (M1 AChR) in AD pathology and possible treatment with selective M1 agonists. It adds indirect support to our earlier findings that M1 agonists such as AF267B could be a highly promising and causal treatment in AD (Caccamo et al., 2006; Fisher, 2008). While this paper represents a major step towards our understanding in M1 AChR-mediated APP processing, I would like to address the following points:

1. Carbachol in the M1 knockout mice increased Aβ production, probably via stimulation of other non-M1 muscarinic receptor subtypes. It can be speculated that this is not due to its agonistic activity on M3 AChR or some nicotinic receptor subtypes. Furthermore, since it appears that mainly the activation of the M1 AChR is responsible for the decrease in Aβ production, while the M2 and M4 AChR may have an opposite effect, this may explain why treatment with cholinesterase inhibitors lack an effect on Aβ production in AD patients. Notably, such treatments increase synaptic ACh that will interact with all cholinergic receptor subtypes.

2. The role of M1 AChR on cognitive functions or effects on tau hyperphosphorylation were not reported in this study in spite of the major role of this receptor in modulating these two major hallmarks of AD (Caccamo et al., 2006).

3. AF267B (originated from our lab, >99.9 percent chemical and enantiomeric purity) was shown in our laboratory to be a selective functional M1 agonist, both in vitro and in vivo (see my comments to Alzforum). Furthermore, AF267B is also specific for muscarinic receptors, unlike several selective allosteric M1 agonists reported recently that interact with some other G protein-coupled receptors. However, the authors refer to Jones and colleagues’ claim of similar activities on M1 and M3 AChRs using AF267B (though source and purity were not reported; see Jones et al., 2008).

4. M1 selective agonists represent a rational treatment for AD both in treating cognitive deficits and as potential disease modifiers on AD hallmarks (Fisher, 2008). The previous clinical experience in AD with muscarinic agonists was disappointing. However, it is important to emphasize that the compounds that failed in clinical trials lacked selectivity for the M1 AChR, had major side effects, and some had poor pharmacokinetics. Thus, the question whether M1 agonists are useful treatments in AD was not really addressed so far in AD patients. Based on a plethora of recent studies, the M1 AChR is a promising target for future drug development in AD and was prematurely abandoned by major pharma. Unfortunately, recently major pharma preferred other strategies rather than the M1 therapeutic strategy in their drug development programs to treat AD.

5. Given some major recent disappointments in Phase 2 and 3 studies with compounds that target at best one hallmark but ignore the others in AD, it is imperative and timely "to go back to the drawing board." Due to an elusive etiology, it is imperative to treat comprehensively all major hallmarks, regardless of the real culprit. In this context, M1 selective agonists may provide such a therapy. Notably, AF267B, tested successfully in three Phase 1 and Phase 2a studies (not AD), is the first low-molecular-weight monotherapy that targets comprehensively the major hallmarks of AD (cognitive dysfunctions, cholinergic hypofunction, Aβ and tau pathologies). Clinical studies in AD patients are timely and justified to explore the role of AF267B and some other M1 selective agonists in AD treatment.

References:
Fisher A. M1 muscarinic agonists target major hallmarks of Alzheimer's disease—the pivotal role of brain M1 receptors. Neurodegener Dis. 2008;5(3-4):237-40. 2008. Review. Abstract

Fisher A. Cholinergic treatments with emphasis on M1 muscarinic agonists as potential disease-modifying agents for Alzheimer's disease. Neurotherapeutics, 2008. Abstract

Caccamo A, Oddo S, Billings LM, Martinez-Coria H, Fisher A, LaFerla FM. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 2006;49:671-682. Abstract

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