Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer's disease

Overk, Cassia R.; Felder, Christian C.; Tu, Yuan; Schober, Doug A.; Bales, Kelly R.; Wuu, Joanne; Mufson, Elliott J.

doi:10.1016/j.jchemneu.2010.03.005

Cited by 34 publications

(31 citation statements)

References 72 publications

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“…L left, R right, Ant anterior, Pos posterior, Sup superior compared to controls, but similar in neocortical areas [36], the relative pattern could suggest a loss of M1/M4 receptors in the medial temporal and cholinergic rich basal forebrain, accompanied by either preservation or an increase in cortical M1/M4 receptor availability. These changes thus may reflect a compensatory response to maintain basocortical cholinergic function given that loss of pre-synaptic receptors usually results in compensatory up-regulation of post-synaptic receptors [35]. Alternatively, the relative preservation or increase may also be the result of a postulated bidirectional modulatory effect between beta amyloid and M1 receptors in the frontal and parietal areas [41].…”

Section: Discussionmentioning

confidence: 99%

“…Utilising selective muscarinic ligands such as 3 H-pirenzepine (M1), others reported similar binding in various cortical [5] and frontal [50] regions relative to controls, though striatal binding was significantly higher [5,40]. With 3 H-oxotremorine-M (M1), increased receptor concentrations in cortical regions were found [35]. For 3 H-AF-DX116 (M2), AD uptake was lower in frontal, temporal and hippocampal areas [5], while elevated levels of 3 H-AF-DX384 (M2/M4) in the striatum and 125 I-(R, R)-QNB (M1/M4) in the claustrum, insula and cingulate cortex were observed compared to controls [40].…”

Section: Discussionmentioning

confidence: 99%

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Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

et al. 2015

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Alzheimer's disease (AD) is characterised by deficits in cholinergic neurotransmission and subsequent receptor changes. We investigated (123)I-iodo-quinuclidinyl-benzilate (QNB) SPECT images using spatial covariance analysis (SCA), to detect an M1/M4 receptor spatial covariance pattern (SCP) that distinguished AD from controls. Furthermore, a corresponding regional cerebral blood flow (rCBF) SCP was also derived. Thirty-nine subjects (15 AD and 24 healthy elderly controls) underwent (123)I-QNB and (99m)Tc-exametazime SPECT. Voxel SCA was simultaneously applied to the set of smoothed/registered scans, generating a series of eigenimages representing common intercorrelated voxels across subjects. Linear regression identified individual M1/M4 and rCBF SCPs that discriminated AD from controls. The M1/M4 SCP showed concomitant decreased uptake in medial temporal, inferior frontal, basal forebrain and cingulate relative to concomitant increased uptake in frontal poles, occipital, pre-post central and precuneus/superior parietal regions (F1,37 = 85.7, p < 0.001). A largely different perfusion SCP was obtained showing concomitant decreased rCBF in medial and superior temporal, precuneus, inferior parietal and cingulate relative to concomitant increased rCBF in cerebellum, pre-post central, putamen, fusiform and brain stem/midbrain regions (F1,37 = 77.5, p < 0.001). The M1/M4 SCP expression correlated with the duration of cognitive symptoms (r = 0.90, p < 0.001), whereas the rCBF SCP expression negatively correlated with MMSE, CAMCOG and CAMCOGmemory (r ≥ |0.63|, p ≤ 0.006). (123)I-QNB SPECT revealed an M1/M4 basocortical covariance pattern, distinct from rCBF, reflecting the duration of disease rather than current clinical symptoms. This approach could be more sensitive than univariate methods in characterising the cholinergic/rCBF changes that underpin the clinical phenotype of AD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

et al. 2015

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“…35 S] binding in native tissue was performed essentially as described previously (Overk et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Characterization of LY593093, an M1 Muscarinic Acetylcholine Receptor-Selective Partial Orthosteric Agonist

Watt

Schober²,

Hitchcock³

et al. 2011

J Pharmacol Exp Ther

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Alzheimer's disease and schizophrenia are characterized by expression of psychotic, affective, and cognitive symptoms. Currently, there is a lack of adequate treatment for the cognitive symptoms associated with these diseases. Cholinergic signaling and, in particular, M1 muscarinic acetylcholine receptor (m1AChR) signaling have been implicated in the regulation of multiple cognitive domains. Thus, the M1AChR has been identified as a therapeutic drug target for diseases, such as schizophrenia and Alzheimer's disease, that exhibit marked cognitive dysfunction as part of their clinical manifestation. Unfortunately, the development of selective M1 agonist medications has not been successful, mostly because of the highly conserved orthosteric acetylcholine binding site among the five muscarinic receptor subtypes. More recent efforts have focused on the development of allosteric M1AChR modulators that target regions of the receptor distinct from the orthosteric site that are less conserved between family members. However, orthosteric and allosteric ligands may differentially modulate receptor function and ultimately downstream signaling pathways. Thus, the need for highly selective M1AChR orthosteric agonists still exists, not only as a potential therapeutic but also as a pharmacological tool to better understand the physiologic consequences of M1AChR orthosteric activation. Here, we describe the novel, potent and selective M1AChR orthosteric partial agonist. This compound demonstrates modest to no activity at the other muscarinic receptor subtypes, stimulates G␣ qcoupled signaling events as well as ␤-arrestin recruitment, and displays significant efficacy in in vivo models of cognition.

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“…30 [ 3 H]-Oxotremorine-M radioligand binding studies found M 1 mAChR expression to be elevated in the AD cortical tissue, indicative of compensatory upregulation in response to a reduction in ACh levels. It was also found that while there was no correlation between function of M 1 mAChRs and the degree of cognitive impairment, a negative correlation between M 1 mAChR functional activity and severity of neuropathology (based on post-mortem neurofibrillary tangle analysis) was observed, adding further weight to the argument for selective targeting of this receptor in the treatment of AD.…”

Section: ■ the Cholinergic Hypothesis Of Memory Dysfunctionmentioning

confidence: 99%

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Davie

Christopoulos

Scammells

2013

ACS Chem. Neurosci.

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Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M 1 muscarinic acetylcholine receptor (M 1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M 1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M 1 mAChR, comprehensively summarize and critically evaluate the M 1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. KEYWORDS: M 1 mAChR, allosteric ligands, Alzheimer's disease, schizophrenia, cognitive deficits, memory T he muscarinic acetylcholine receptor (mAChR) family is a group of rhodopsin-like (Family A) G protein-coupled receptors (GPCRs) consisting of five distinct subtypes M 1 −M 5 . Activation of the M 1 , M 3 , and M 5 receptor subtypes primarily results in coupling to the G q/11 family of G proteins, activation of phospholipase C (PLC), release of inositol-1,4,5-trisphosphate (IP 3 ), and subsequent mobilization of intracellular calcium Ca 2+ . Activation of the M 2 and M 4 receptor subtypes primarily results in coupling to the G i/o family of G proteins, inhibition of adenylate cyclase (AC), reduction in cyclic AMP (cAMP), and a decrease in neurotransmitter release via the blockage of voltage-gated calcium channels (Figure 1). These pathways represent a generalized view of each receptor's coupling capacity, as all five subtypes couple to a broader range of G protein-and non-G protein-mediated signaling and regulatory pathways, 1 ultimately leading to the regulation of enzymes and neurotransmitters critical for intercellular chemical communication and biological function. In a ...

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Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer's disease

Cited by 34 publications

References 72 publications

Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

Pharmacological Characterization of LY593093, an M1 Muscarinic Acetylcholine Receptor-Selective Partial Orthosteric Agonist

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

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Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer's disease

Cited by 34 publications

References 72 publications

Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

Pharmacological Characterization of LY593093, an M1 Muscarinic Acetylcholine Receptor-Selective Partial Orthosteric Agonist

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

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Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits