Reduction of cerebrospinal fluid amyloid β after systemic administration of M1 muscarinic agonists

Beach, Thomas G.; Walker, Douglas G.; Potter, Pamela E.; Sue, Lucia I.; Fisher, Abraham

doi:10.1016/s0006-8993(01)02484-2

Cited by 65 publications

(47 citation statements)

References 19 publications

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“…We show here that the nonselective agent carbachol as well as the M 1 -selective muscarinic agonist AF267B (Beach et al, 2001;Fisher et al, 2002) both enhance N1 production by primary cultured neurons. This effect was mainly mediated by PKC-coupled M 1 and M 3 but not by PKA-linked M 2 and M 4 muscarinic receptors.…”

Section: Introductionmentioning

confidence: 53%

“…The selective M 1 receptor agonist AF267B increases N1 production in HEK293 cells and primary cultured neurons AF267B, developed as a selective M 1 muscarinic agonist (Beach et al, 2001;Fisher et al, 2002), was used to confirm the selective involvement of M 1 muscarinic receptors in N1 recovery in primary cultured neurons and M 1 -expressing HEK293 cells. AF267B increased the amount of N1 recovered in an atropinesensitive manner in both M 1 -expressing HEK293 cells (Fig.…”

Section: Endogenous Muscarinic Receptor Activation Increases N1 Recovmentioning

confidence: 99%

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M₁and M₃Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity

Cissé¹,

Sunyach²,

Slack³

et al. 2007

J. Neurosci.

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The cellular prion protein (PrP c ) undergoes a physiological processing yielding the N-terminal fragment referred to as N1, the production of which can be constitutive or protein kinase C regulated. We show that activation of endogenous muscarinic receptors by carbachol and by the M 1 -selective agonist AF267B increases N1 recovery in an atropine-sensitive manner, in mouse embryonic primary neurons. To identify the muscarinic receptor subtype involved, we used human embryonic kidney HEK293 (HEK) cells stably overexpressing M 1 , M 2 , M 3 , or M 4 receptor subtype. Carbachol and the selective M 1 agonist AF267B dose dependently increased N1 release by HEK-M 3 and HEK-M 1 cells, respectively, whereas carbachol did not modify N1 production by HEK-M 2 or HEK-M 4 cells. We demonstrate that the increase of N1 was not attributable to modified trafficking to the membrane of either PrP c or the disintegrin metalloproteases ADAM10 or ADAM17. Furthermore, we establish that carbachol affects the overall phosphorylation of ADAM17 on its threonine and tyrosine but not serine residues, whereas levels of phosphorylated ADAM9 were not affected. Interestingly, carbachol also increases the hydrolysis of the fluorimetric substrate JMV2770, which mimicked the sequence encompassing the N1 site cleavage and was shown previously to behave as an ADAM protease substrate. Mutations of threonine 735 but not of tyrosine 702 of the ADAM17 cytoplasmic tail abolishes the carbachol-induced increase of N1, ADAM17 phosphorylation, and JMV2770-hydrolyzing activity in M 1 -and M 3 -expressing HEK293 cells. Thus, our data provide strong evidence that muscarinic receptor activation increases the physiological processing of PrP c by upregulating the phosphorylation state and activity of ADAM17 protease.

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Section: Introductionmentioning

confidence: 53%

Section: Endogenous Muscarinic Receptor Activation Increases N1 Recovmentioning

confidence: 99%

M₁and M₃Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity

Cissé¹,

Sunyach²,

Slack³

et al. 2007

J. Neurosci.

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“…Thus, in rabbits, where the sequence of A␤42 is similar to humans, the three M1 selective agonists AF102B, AF267B and AF150(S) decreased A␤40, whereas AF267B and AF150(S) also reduced levels of A␤42 in the CSF without changing ␣-APPs. 107 Lesioning the cholinergic nucleus basalis magnocellularis in rabbits with a selective cholinergic immunotoxin results in cortical cholinergic deafferentation and cortical A␤ deposition. 108 The A␤ deposits are primarily vascular, with occasional perivascular plaques.…”

Section: In Vivo Studiesmentioning

confidence: 99%

“…The clinical significance of these findings with M1 agonists remains to be established, yet it is possible that the observed effect of these agonists reflect the outcome of a therapy designed to alter APP processing. Notably the preclinical data (e.g., normal and lesioned rabbits, respectively) 107,108 showed that a decrease in the CSF A␤ induced by M1 agonists is paralleled by a cortical decrease in soluble A␤ levels.…”

Section: Some Relevant Clinical Studies On Ad Modificationmentioning

confidence: 99%

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

2008

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Summary:The only prescribed drugs for treatment of Alzheimer's disease (AD) are acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, and tacrine) and memantine, an NMDA antagonist. These drugs ameliorate mainly the symptoms of AD, such as cognitive impairments, rather than halting or preventing the causal neuropathology. There is currently no cure for AD and there is no way to stop its progression, yet there are numerous therapeutic approaches directed against various pathological hallmarks of AD that are extensively being pursued. In this context, the three major hallmark characteristics of AD (i.e., the CNS cholinergic hypofunction, formation of ␤-amyloid plaques, and tangles containing hyperphosphorylated tau proteins) are apparently linked. Such linkages may have therapeutic implications, and this review is an attempt to analyze these versus the advantages and drawbacks of some cholinergic compounds, such as acetylcholinesterase inhibitors, M1 muscarinic agonists, M2 antagonists, and nicotinic agonists. Among the reviewed treatments, M1 selective agonists emerge, in particular, as potential disease modifiers.

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“…[11][12][13][14] Also, treatment with the selective M 1 R agonist AF267B reduces the A␤ levels in the cerebrospinal fluid and cerebrovasculature in rabbits. 15,16 Evidence from our laboratory shows that long-term treatment with this compound reverses cognitive impairments and decreases A␤ and tau pathological features in the 3xTgAD mice. 17 Similarly, the administration of the muscarinic agonist RS86 to rats decreases APP levels in the cortex and hippocampus and increases the APP␣ level in the cerebrospinal fluid.…”

mentioning

confidence: 98%

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Medeiros

Kitazawa

Caccamo

et al. 2011

The American Journal of Pathology

106

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Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and ␤-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M 1 receptors (M 1 Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M 1 Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M 1 R ؊/؊ mice. Our data show that M 1 R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M 1 R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar A␤ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1 R were attributed to changes in the glycogen synthase kinase 3␤ and protein kinase C activities. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive impairment and dementia. The neuropathological hallmarks of AD are amyloid plaques, composed of ␤-amyloid (A␤) peptides, and neurofibrillary tangles, composed of the hyperphosphorylated tau protein. The deposition of fibrillar A␤ in the cerebrovasculature, a condition known as cerebral amyloid angiopathy (CAA), is also a prominent feature of AD. Together with associated processes, such as inflammation and oxidative stress, these pathological cascades contribute to loss of synaptic integrity and progressive neurodegeneration. 1Restoring cholinergic dysfunction has been a primary means of improving the cognitive decline in AD because four of the five Food and Drug Administration-approved drugs are acetylcholinesterase inhibitors, with the notable exception of memantine.2 Acetylcholinesterase inhibitors provide mild symptomatic relief but eventually lose efficacy over time, most likely because they are not disease-modifying agents.1 Alternatively, recent evidence 3,4 indicates that stimulation of muscarinic acetylcholine receptors, in particular the M 1 receptor (M 1 R), restores cognition and attenuates AD-like pathological features in several different animal models, rendering it an attractive therapeutic approach for AD. The M 1 R is the most abundant muscarinic acetylcholine receptor subtype in the cerebral cortex and hippocampus, the two main brain reSupported by grants from the NIH (NIH/NIAMS K99AR054695 to M.K.; NIH/NIA R01AG20335 and Program Project AG00538 to F.M.L.).

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Reduction of cerebrospinal fluid amyloid β after systemic administration of M1 muscarinic agonists

Cited by 65 publications

References 19 publications

M₁and M₃Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity

M₁and M₃Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

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Reduction of cerebrospinal fluid amyloid β after systemic administration of M1 muscarinic agonists

Cited by 65 publications

References 19 publications

M1and M3Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity

M1and M3Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

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M₁and M₃Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity

M₁and M₃Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity