. Altered hippocampal muscarinic receptors in acetylcholinesterase-deficient mice. Ann Neurol. 2003 Jun;53(6):788-96. PubMed.

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  1. The authors report that acetylcholinesterase (AChE)-deficient mice have markedly decreased expression of muscarinic receptor (mAChR) subtypes (M1, M2 and M4) in brain regions associated with memory. This was accompanied by a robust decrease in mAChR (probably M1)-mediated stimulation of ERK, a pathway that, among other things, is associated with synaptic plasticity, memory and amyloidogenesis. This is an important and timely paper that deals with a major problem in Alzheimer’s disease (AD) treatment related to the question why chronic use of AChE inhibitors (AChEIs) has only modest efficacy on cognition and daily functioning, and why the effects of such treatments wear off over time. The authors attribute this to mAChR downregulation.

    The cholinergic deficiency in AD, a major hallmark of the disease, indicates that disease progression associated with loss of the cholinergic neurons and decreases in acetylcholine (ACh) will limit the therapeutic potential of AChEIs to only a fraction of AD patients and to a limited time period. In this context, it was long recognized that downregulation of mAChR can occur following prolonged inhibition of AChE and elevation of synaptic ACh levels. The present paper further emphasizes this relationship between inhibition of the neurotransmitter’s degradation and downregulation of its receptor subtypes. Thus, in addition to the natural course of AD (i.e., disease progression and cholinergic neurodegeneration), chronic treatment with AChEIs may be a two-edged sword because it induces, among other things, a functional downregulation of cortical and hippocampal M1 mAChR, which has been implicated in the regulation of cognition and psychosis.

    This conclusion reinforces the merits of alternative manipulations of the cholinergic system in AD therapy. In particular, selective M1 muscarinic agonists may be a rational treatment in addition to AChEIs (Fisher et al, 2002). Highly selective partial M1 agonists (M1>>>M3>M2>M4) should be preferred as such compounds do not cause M1 mAChR downregulation (Fisher et al, 2002; abstract at ADPD conference, 2003, Seville, see ARF related news story). Theoretically, M1 muscarinic agonists are independent of brain ACh levels and thus less affected by the extent of degeneration of presynaptic cholinergic terminals. Therefore, M1 muscarinic agonists might allow one to continue treating the cognitive decline when AChEIs no longer work due to disease progression and down-regulation of M1 mAChR. Furthermore, M1 selective agonists can be useful in AD both in treatment and as disease-modifying agents. The use of new and selective M1 agonists free of the drawbacks of prior agonists that failed in AD may revive this treatment modality and provide a significant added value to AChEIs in AD.

    References:

    . Impact of muscarinic agonists for successful therapy of Alzheimer's disease. J Neural Transm Suppl. 2002;(62):189-202. PubMed.