Whether or not the mild cognitive deficits associated with aging or the severe memory loss in AD depend, at least partly, on the loss of muscarinic receptors or change in their function is a controversial topic. Age-related loss of muscarinic receptors in rat neocortex and hippocampus is still a matter of debate, with the majority of the studies reporting no changes, and a few reporting a decrease or even an increase in binding sites.44,196 In a recent PET study using N-[11C]methyl-4-piperidyl benzilate, a decrease in muscarinic cholinergic receptor binding in vivo was observed in several brain areas of aged conscious monkeys.9 Variation in animal species, rat strain, age of the animal, technique employed and the mAChR subtype studied as well as the poor specificity of the ligands towards individual mAChR subtypes, all contribute to the controversy. For example, Quirion and coworkers151 showed that memory-impaired, aged Long-Evans rats have higher levels of cortical and hippocampal presynaptic mAChR autoreceptors, determined indirectly through the modulation of ACh release, while other authors, using specific antibodies,37 did not find any change in the number of mAChRs in the same strain of rats. This latter finding is in line with the observation that cholinergic depletion in the neocortex accomplished by NBM lesion is not accompanied by loss in mAChR immunoreactivity.194,216 On the other hand, Gill and Gallagher 4 found a significant age-related reduction in M2 binding sites in the basal forebrain (MS/DBB) and brainstem (PPTN), and the reduction in the basal forebrain was correlated with spatial learning impairment. Both of these ascending cholinergic systems seem to be impaired in the aged rat brain. Since in the MS/ DBB complex M2 receptors are not exclusively located on cholinergic cells,109 decreased M2 receptor binding in aged rats may reflect composite alterations affecting cholinergic and non cholinergic (presumably GABAergic) cells. The decreased density in M2 binding within the basal forebrain in normal aging is consistent with several studies in rodents and primates.7,137 Taken together all of these findings led to the conclusion that postsynaptic receptors are largely unchanged in the aging brain,10 8 but their function may be impaired,58 while there is no consensus regarding the changes in the M2 receptor subtype.
A reduction in the coupling efficiency to the second messenger system(s), instead of alterations in the number of mAChRs could be the age-related event responsible for cholinergic-related memory dysfunctions. Indeed, it has been shown that the efficiency of hippocampal muscarinic receptors coupling to phosphoinositide (PI) turnover is decreased in cognitively impaired aged rats and this change is highly correlated with the spatial learning index,37 while there is no difference in the levels of muscarinic receptor proteins between young and aged rats or in rats with impaired spatial learning.
Only recently has information been obtained regarding the molecular subtypes of mAChRs affected by AD. Most studies on muscarinic receptor alterations in AD have concentrated on changes in the pharmacological binding sites in the cortex of aged normal controls and of AD postmortem brains. In AD, the severe loss of cortical cholinergic innervation is accompanied by depletion of m2 receptors, with a relative stability of m1 receptors.118'182 These findings, again, led to the concept that postsynaptic receptors are largely unchanged58,118 in AD, but may not be functional.58-60 Quantitative immunoprecipitation followed by radioligand binding demonstrated that m2 immunoreactivity is decreased, while the m4 receptor is up-regulated.59 On the other hand, Mufson and coworkers135 demonstrated that despite the extensive reduction in cholinergic basal forebrain neurons, the cellular expression of the m2 receptor is not significantly altered within the basal forebrain of AD patients, suggesting that the reduced levels of the m2 receptor seen in AD cortex probably reflect changes in other neuronal populations. Some of the m2-expressing pyramidal neurons may undergo degeneration in AD and thus contribute to the overall loss of m2 receptors in these patients. Very recently, using muscarinic receptor binding in vivo with [11C]NMBP and PET in healthy volunteers and AD patients,225 it was demonstrated that muscarinic receptor binding shows an age-related decline, but no evidence of regional changes in AD patients, a finding that is largely in agreement with post-mortem data. At variance with these results, Lai et al105 in a postmortem investigation found a decrease in M2 receptor density in the frontal cortex of AD patients with no change in M1 receptors. However, M2 receptor density was increased in the frontal cortex of patients with psychotic symptoms compared with those without these symptoms.
The possibility that muscarinic postsynaptic receptors undergo upregulation following degeneration of the cholinergic fibres141 must be also taken into consideration. It could be speculated that in the AD brain postsynaptic compensatory processes are set forward as a response to a decrease in presynaptic activity. Interestingly,80,206 it was demonstrated that the mRNA of the m1 subtype increased in the temporal cortex ofAD patients, with no changes in m2, m3, and m4 mRNA.206 A defect in the coupling of muscarinic receptors to GTP-binding protein,177,207 and/or defective receptor-G protein/phospholipase C coupling56 in AD brain has also been demonstrated.
Whatever the distribution and dynamics of mAChRs in AD patients, Nitsch and coworkers140 provided the first and most direct link between muscarinic receptors and AD when they showed that M1- and M3-mediated muscarinic stimulation of cortical neurons promotes the processing of the amyloid precursor protein (APP) by the y-secretase pathway. This pathway splits the APP molecules in the middle of the Ap domain, therefore precluding the subsequent release of insoluble Ap.89 These experiments suggest that loss of mAChRs subtypes during aging and AD may increase the deposition of insoluble Ap to form plaques.
It must be mentioned that mAChRs are present not only on neurons, but also on glial cells, and are associated with cerebral microvasculature.196 In contrast to neurons, an increase in the number and intensity of mAChRs-positive astrocytes in cortex and hippocampus of aged rats has been reported.193 Furthermore, Messamore and coworkers124 showed, in autopsy brain sections from AD patients, that astrocytes associated with senile plaques possess muscarinic acetylcholine receptors. A brain-specific inflammatory reaction, presumably to the p-amyloid plaques, is an important pathogenetic component of AD (for review see ref. 123). The inflammatory reaction is characterized by activation of microglial cells and astrocytes. The activation of glial cells possessing muscarinic receptors may explain the controversial results on mAChRs expression obtained in aging and AD brain.
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