p(HGNC:CHRM1)

Entity

Name

CHRM1

Namespace

hgnc

Namespace Version

20180906

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Two novel M4-selective compounds, VU10010 and LY2033298, represented a breakthrough when they were described in 2008.84,85 VU10010 is a potent M4-selective PAM that increases affinity/efficacy of ACh to promote M4 mAChR activation. PubMed:24511233

Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD PubMed:24511233

Another early allosteric agonist, TBPB (1-(1’-(2-methylbenzyl) -1,4’-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1), also exhibited impressive selectivity for M1 mAChRs and potentiated NMDA receptor currents in CA1 hippocampal cells. PubMed:24511233

Subsequent optimization produced two analogs of AC-42 (AC-260584 and 77-LH-28-1), which maintained M1 selectivity and possessed properties suitable for use in animal models. Both AC-260584 and 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models PubMed:24511233

The first subtype-selective M1 PAM to be characterized was benzyl quinolone carboxylic acid (BQCA);68 BQCA exhibited high selectivity with no activity at mAChR subtypes M2–M5 and induced up to a 129-fold leftward shift in ACh potency at the M1 mAChR PubMed:24511233

Subsequent optimization produced two analogs of AC-42 (AC-260584 and 77-LH-28-1), which maintained M1 selectivity and possessed properties suitable for use in animal models. Both AC-260584 and 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models PubMed:24511233

Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD PubMed:24511233

The M1 mAChR subtype is the most predominantly expressed mAChR subtype in the CNS and is expressed in several brain regions implicated in the regulation of cognitive processes, including the striatum, prefrontal cortex, and hippocampus. PubMed:24511233

More recently, the M1-selective allosteric agonist VU0357017 was discovered, which displayed improved potency via binding to a novel allosteric site on the M1 mAChR. VU0357017 significantly blocked scopolamine-impaired contextual fear conditioning and enhanced spatial and contextual fear learning PubMed:24511233

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

Moreover, the M1 agonist AF267B can rescue the cognitive impairment and decrease Aβ42 and tau abnormalities in the cortex and hippocampus of a mouse model of AD PubMed:26813123

Moreover, the use of M2 antagonists, such as SCH-57790 and SC-72788, can lead to blockage of M2-mediated inhibition of presynaptic release of ACh, which can activate M1 and nicotinic receptors, ameliorating cognitive impairment in AD PubMed:26813123

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

In fact, Abeta has been shown to induce the uncoupling of M1 mAChR from G-protein, antagonizing the function of M1 mAChR under the pathological conditions of AD[96, 97]. Such an uncoupling may result in decreased signal transduction, reduced levels of sAPPalpha, and increased production of Abeta, triggering a vicious cycle. PubMed:24590577

Stimulation of M1 mAChR by two agonists, carbachol and AF102B, time- and dose-dependently decreases tau phosphorylation in PC12 cells[81]. Chronic treatment with AF267B also alleviates tau pathology in 3×Tg AD mice, possibly by activating PKC and inhibiting GSK-3beta PubMed:24590577

One example is xanomeline, an mAChR agonist with selectivity for the M1 and M4 subtypes. Xanomeline improves working memory in rodents and improves cognition and reduces psychotic episodes in AD patients, but it failed during phase-II clinical trial because of serious side-effects, probably due to simultaneous activation of M1 and M4 mAChRs (M4 > M1) PubMed:24590577

During the past few years, the M1 mAChR allosteric agonists VU0184670 and VU0357017 have been screened out, and have more exciting properties. Both compounds have high solubility in aqueous solutions as well as good CNS penetration, without any agonist or antagonist activity for the M2 and M5 subtypes PubMed:24590577

Nevertheless, a compound developed later, TBPB, selectively activates M1 mAChR in cell lines and shows no agonist activity in any other mAChR subtype. Interestingly, TBPB also potentiates the NMDA-evoked current in hippocampal pyramidal neurons, which is considered to be important for the effect of M1 mAChR on improving cognition. In addition, TBPB shifts the processing of APP in the non-amyloidogenic direction and thereafter decreases neurotoxic Abeta production vitro[120]. PubMed:24590577

Compound 77-LH-28-1 shows relatively higher selectivity for the M1 than for the M2, M4, and M5 subtypes, but retains weak agonist activity for M3 mAChR at high doses. Electrophysiological studies indicate that 77-LH-28-1 increases the activity of hippocampal CA1 pyramidal cells both in vitro and in vivo. Interestingly, unlike other normal orthosteric agonists, 77-LH-28-1 appears to selectively activate M1 mAChR in a distinct signaling pathway PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

During the past few years, the M1 mAChR allosteric agonists VU0184670 and VU0357017 have been screened out, and have more exciting properties. Both compounds have high solubility in aqueous solutions as well as good CNS penetration, without any agonist or antagonist activity for the M2 and M5 subtypes PubMed:24590577

Stimulation of M1 mAChR by two agonists, carbachol and AF102B, time- and dose-dependently decreases tau phosphorylation in PC12 cells[81]. Chronic treatment with AF267B also alleviates tau pathology in 3×Tg AD mice, possibly by activating PKC and inhibiting GSK-3beta PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Conversely, M1 subunit gene expression in single CBF neurons is preserved during the progression of AD (Table 1) [119,126]. The M1 receptor is a most interesting drug target as it links several of the major hallmarks of this disorder, including cholinergic deficiency, cognitive dysfunctions, Ab and tau pathologies. PubMed:18986241

Conversely, M1 subunit gene expression in single CBF neurons is preserved during the progression of AD (Table 1) [119,126]. The M1 receptor is a most interesting drug target as it links several of the major hallmarks of this disorder, including cholinergic deficiency, cognitive dysfunctions, Ab and tau pathologies. PubMed:18986241

Conversely, M1 subunit gene expression in single CBF neurons is preserved during the progression of AD (Table 1) [119,126]. The M1 receptor is a most interesting drug target as it links several of the major hallmarks of this disorder, including cholinergic deficiency, cognitive dysfunctions, Ab and tau pathologies. PubMed:18986241

Interestingly, these M1-deficient mice display increased amphetamine-induced hyperlocomotion and dopamine neurotransmission,47 indicating that M1 modulation may have antipsychotic potential. PubMed:24511233

The M1 mAChR subtype is the most predominantly expressed mAChR subtype in the CNS and is expressed in several brain regions implicated in the regulation of cognitive processes, including the striatum, prefrontal cortex, and hippocampus. PubMed:24511233

Subsequent optimization produced two analogs of AC-42 (AC-260584 and 77-LH-28-1), which maintained M1 selectivity and possessed properties suitable for use in animal models. Both AC-260584 and 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models PubMed:24511233

Interestingly, these M1-deficient mice display increased amphetamine-induced hyperlocomotion and dopamine neurotransmission,47 indicating that M1 modulation may have antipsychotic potential. PubMed:24511233

M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks. PubMed:24511233

Another early allosteric agonist, TBPB (1-(1’-(2-methylbenzyl) -1,4’-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1), also exhibited impressive selectivity for M1 mAChRs and potentiated NMDA receptor currents in CA1 hippocampal cells. PubMed:24511233

M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks. PubMed:24511233

The first subtype-selective M1 PAM to be characterized was benzyl quinolone carboxylic acid (BQCA);68 BQCA exhibited high selectivity with no activity at mAChR subtypes M2–M5 and induced up to a 129-fold leftward shift in ACh potency at the M1 mAChR PubMed:24511233

Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD PubMed:24511233

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

It has been shown that activation of M1 receptors decreases tau hyperphosphorylation via activation of PKC and inhibition of GSK-3β PubMed:26813123

It has been shown that activation of M1 receptors decreases tau hyperphosphorylation via activation of PKC and inhibition of GSK-3β PubMed:26813123

It has been shown that activation of M1 receptors decreases tau hyperphosphorylation via activation of PKC and inhibition of GSK-3β PubMed:26813123

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Activation of M1 mAChR also protects against apoptotic factors in human neuroblastoma SH-SY5Y cells, such as DNA damage, oxidative stress, caspase activation, and mitochondrial impairment[83]. In addition, apoptosis induced by serum deprivation is blocked by M1 mAChR activation in a phosphoinositide 3-kinase- and MAPK/ERKindependent manner PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory PubMed:24590577

At the cellular level, M1 mAChR is highly expressed in striatonigral, striatopallidal, and glutamatergic pyramidal neurons, especially in extrasynaptic regions. This localization of M1 mAChR is consistent with the cholinergic modulation of glutamatergic neurotransmission PubMed:24590577

Interestingly, stimulation of M1 mAChR by agonists has been found to enhance sAPPalpha generation and reduce Abeta production[61-70]. Protein kinase C (PKC) is well-known to be activated upon stimulation of M1 mAChR. PKC may promote the activity of alpha-secretase[71] and the traffi cking of APP from the Golgi/ trans-Golgi network to the cell surface PubMed:24590577

Interestingly, stimulation of M1 mAChR by agonists has been found to enhance sAPPalpha generation and reduce Abeta production[61-70]. Protein kinase C (PKC) is well-known to be activated upon stimulation of M1 mAChR. PKC may promote the activity of alpha-secretase[71] and the traffi cking of APP from the Golgi/ trans-Golgi network to the cell surface PubMed:24590577

Interestingly, stimulation of M1 mAChR by agonists has been found to enhance sAPPalpha generation and reduce Abeta production[61-70]. Protein kinase C (PKC) is well-known to be activated upon stimulation of M1 mAChR. PKC may promote the activity of alpha-secretase[71] and the traffi cking of APP from the Golgi/ trans-Golgi network to the cell surface PubMed:24590577

When APP/PS1/tau triple transgenic (3×Tg) AD mice are treated with the selective M1 mAChR agonist AF267B, the endogenous level of BACE1 decreases via an unclear mechanism, accompanied by a decreased Abeta level[77]. However, another study found that stimulation of M1 mAChR upregulates BACE1 levels in SK-SH-SY5Y cells via the PKC and MAPK signaling cascades[78]. We recently found that M1 mAChR directly interacts with BACE1 and mediates its proteasomal degradation[79]. These results suggest that M1 mAChR modulates BACE1 in a mixed manner. PubMed:24590577

In addition to inhibiting Abeta generation, activation of M1 mAChR counteracts Abeta-induced neurotoxicity through the Wnt signaling pathway, as Abeta impairs the Wnt pathway and M1 mAChR stimulation inactivates GSK-3beta via PKC activation, stabilizes beta-catenin, and induces the expression of Wnt-targeting genes engrailed and cyclin-D1 for neuron survival PubMed:24590577

Some studies suggest that M1 mAChR stimulation also leads to activation of ERK1/2, which can modulate alpha-secretase activity and APP processing[67, 73], PubMed:24590577

though there are contradictory findings showing that the alpha-secretase-mediated APP processing via M1 mAChR stimulation is not modulated by the ERK1/MEK cascade[71]. On the other hand, loss of M1 mAChR increases amyloidogenic APP processing in neurons and promotes brain Abeta plaque pathology in a mouse model of AD PubMed:24590577

When APP/PS1/tau triple transgenic (3×Tg) AD mice are treated with the selective M1 mAChR agonist AF267B, the endogenous level of BACE1 decreases via an unclear mechanism, accompanied by a decreased Abeta level[77]. However, another study found that stimulation of M1 mAChR upregulates BACE1 levels in SK-SH-SY5Y cells via the PKC and MAPK signaling cascades[78]. We recently found that M1 mAChR directly interacts with BACE1 and mediates its proteasomal degradation[79]. These results suggest that M1 mAChR modulates BACE1 in a mixed manner. PubMed:24590577

When APP/PS1/tau triple transgenic (3×Tg) AD mice are treated with the selective M1 mAChR agonist AF267B, the endogenous level of BACE1 decreases via an unclear mechanism, accompanied by a decreased Abeta level[77]. However, another study found that stimulation of M1 mAChR upregulates BACE1 levels in SK-SH-SY5Y cells via the PKC and MAPK signaling cascades[78]. We recently found that M1 mAChR directly interacts with BACE1 and mediates its proteasomal degradation[79]. These results suggest that M1 mAChR modulates BACE1 in a mixed manner. PubMed:24590577

When APP/PS1/tau triple transgenic (3×Tg) AD mice are treated with the selective M1 mAChR agonist AF267B, the endogenous level of BACE1 decreases via an unclear mechanism, accompanied by a decreased Abeta level[77]. However, another study found that stimulation of M1 mAChR upregulates BACE1 levels in SK-SH-SY5Y cells via the PKC and MAPK signaling cascades[78]. We recently found that M1 mAChR directly interacts with BACE1 and mediates its proteasomal degradation[79]. These results suggest that M1 mAChR modulates BACE1 in a mixed manner. PubMed:24590577

In addition to inhibiting Abeta generation, activation of M1 mAChR counteracts Abeta-induced neurotoxicity through the Wnt signaling pathway, as Abeta impairs the Wnt pathway and M1 mAChR stimulation inactivates GSK-3beta via PKC activation, stabilizes beta-catenin, and induces the expression of Wnt-targeting genes engrailed and cyclin-D1 for neuron survival PubMed:24590577

In addition to inhibiting Abeta generation, activation of M1 mAChR counteracts Abeta-induced neurotoxicity through the Wnt signaling pathway, as Abeta impairs the Wnt pathway and M1 mAChR stimulation inactivates GSK-3beta via PKC activation, stabilizes beta-catenin, and induces the expression of Wnt-targeting genes engrailed and cyclin-D1 for neuron survival PubMed:24590577

In addition to inhibiting Abeta generation, activation of M1 mAChR counteracts Abeta-induced neurotoxicity through the Wnt signaling pathway, as Abeta impairs the Wnt pathway and M1 mAChR stimulation inactivates GSK-3beta via PKC activation, stabilizes beta-catenin, and induces the expression of Wnt-targeting genes engrailed and cyclin-D1 for neuron survival PubMed:24590577

Stimulation of M1 mAChR by two agonists, carbachol and AF102B, time- and dose-dependently decreases tau phosphorylation in PC12 cells[81]. Chronic treatment with AF267B also alleviates tau pathology in 3×Tg AD mice, possibly by activating PKC and inhibiting GSK-3beta PubMed:24590577

Activation of M1 mAChR also protects against apoptotic factors in human neuroblastoma SH-SY5Y cells, such as DNA damage, oxidative stress, caspase activation, and mitochondrial impairment[83]. In addition, apoptosis induced by serum deprivation is blocked by M1 mAChR activation in a phosphoinositide 3-kinase- and MAPK/ERKindependent manner PubMed:24590577

Activation of M1 mAChR also protects against apoptotic factors in human neuroblastoma SH-SY5Y cells, such as DNA damage, oxidative stress, caspase activation, and mitochondrial impairment[83]. In addition, apoptosis induced by serum deprivation is blocked by M1 mAChR activation in a phosphoinositide 3-kinase- and MAPK/ERKindependent manner PubMed:24590577

Activation of M1 mAChR also protects against apoptotic factors in human neuroblastoma SH-SY5Y cells, such as DNA damage, oxidative stress, caspase activation, and mitochondrial impairment[83]. In addition, apoptosis induced by serum deprivation is blocked by M1 mAChR activation in a phosphoinositide 3-kinase- and MAPK/ERKindependent manner PubMed:24590577

Nevertheless, a compound developed later, TBPB, selectively activates M1 mAChR in cell lines and shows no agonist activity in any other mAChR subtype. Interestingly, TBPB also potentiates the NMDA-evoked current in hippocampal pyramidal neurons, which is considered to be important for the effect of M1 mAChR on improving cognition. In addition, TBPB shifts the processing of APP in the non-amyloidogenic direction and thereafter decreases neurotoxic Abeta production vitro[120]. PubMed:24590577

Conversely, M1 subunit gene expression in single CBF neurons is preserved during the progression of AD (Table 1) [119,126]. The M1 receptor is a most interesting drug target as it links several of the major hallmarks of this disorder, including cholinergic deficiency, cognitive dysfunctions, Ab and tau pathologies. PubMed:18986241

Conversely, M1 subunit gene expression in single CBF neurons is preserved during the progression of AD (Table 1) [119,126]. The M1 receptor is a most interesting drug target as it links several of the major hallmarks of this disorder, including cholinergic deficiency, cognitive dysfunctions, Ab and tau pathologies. PubMed:18986241

Conversely, M1 subunit gene expression in single CBF neurons is preserved during the progression of AD (Table 1) [119,126]. The M1 receptor is a most interesting drug target as it links several of the major hallmarks of this disorder, including cholinergic deficiency, cognitive dysfunctions, Ab and tau pathologies. PubMed:18986241