M1 Muscarinic Receptor Activation Rescues β-Amyloid-Induced Cognitive Impairment through AMPA Receptor GluA1 Subunit

Zhao, Lijie; Chen, Mu-Wen; Qian, Yue; Yang, Qianhao; Ge, Yan-Hui; Chen, Hongzhuan; Qiu, Yu

doi:10.1016/j.neuroscience.2019.04.007

Cited by 11 publications

(4 citation statements)

References 44 publications

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“…M1 and M2 are the most abundant muscarinic ACh receptors subtypes in the central nervous system, which are significantly correlated with memory impairments (Zhang et al, 2007). M1 receptors have long been identified as a potential therapeutic target for treating cognitive impairment in AD (Konar et al, 2019;Zhao et al, 2019). M2 receptors play a major role in modulating cholinergic tone, and broadly impacting circuit function and M2 receptors are also the most likely candidates to mediate the muscarinic suppression of GABA release in the hippocampus (Lebois et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Electro-Acupuncture Improve the Early Pattern Separation in Alzheimer’s Disease Mice via Basal Forebrain-Hippocampus Cholinergic Neural Circuit

Dai

et al. 2022

Front. Aging Neurosci.

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ObjectivesTo explore the effect of electro-acupuncture (EA) treatment on pattern separation and investigate the neural circuit mechanism involved in five familial mutations (5 × FAD) mice.MethodsFive familial mutations mice were treated with EA at Baihui (DU20) and Shenting (DU24) acupoints for 30 min each, lasting for 4 weeks. Cognitive-behavioral tests were performed to evaluate the effects of EA treatment on cognitive functions. 1H-MRS, Nissl staining, immunohistochemistry, and immunofluorescence were performed to examine the cholinergic system alteration. Thioflavin S staining and 6E10 immunofluorescence were performed to detect the amyloid-β (Aβ). Furthermore, hM4Di designer receptors exclusively activated by designer drugs (DREADDs) virus and long-term clozapine-N-oxide injection were used to inhibit the medial septal and vertical limb of the diagonal band and dentate gyrus (MS/VDB-DG) cholinergic neural circuit. Cognitive-behavioral tests and immunofluorescence were performed to investigate the cholinergic neural circuit mechanism of EA treatment improving cognition in 5 × FAD mice.ResultsElectro-acupuncture treatment significantly improved spatial recognition memory and pattern separation impairment, regulated cholinergic system via reduction neuron loss, upregulation of choline/creatine, choline acetyltransferase, vesicular acetylcholine transporter, and downregulation of enzyme acetylcholinesterase in 5 × FAD mice. Aβ deposition was reduced after EA treatment. Subsequently, the monosynaptic hM4Di DREADDs virus tracing and inhibiting strategy showed that EA treatment activates the MS/VDB-DG cholinergic neural circuit to improve the early pattern separation. In addition, EA treatment activates this circuit to upregulating M1 receptors positive cells and promoting hippocampal neurogenesis in the dentate gyrus (DG).ConclusionElectro-acupuncture could improve the early pattern separation impairment by activating the MS/VDB-DG cholinergic neural circuit in 5 × FAD mice, which was related to the regulation of the cholinergic system and the promotion of neurogenesis by EA treatment.

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Section: Discussionmentioning

confidence: 99%

Electro-Acupuncture Improve the Early Pattern Separation in Alzheimer’s Disease Mice via Basal Forebrain-Hippocampus Cholinergic Neural Circuit

Dai

et al. 2022

Front. Aging Neurosci.

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“…For example, activation of M1 receptors promotes the membrane insertion of GluA1 through phosphorylation of S845, a critical site for AMPAR trafficking to the synapse. 71 In that animal model, M1 receptor activation reversed learning and memory impairments through the modulation of GluA1 trafficking.…”

Section: Role Of G Lua1 In Ab Err Ant Synap Ti C Pl a S Ti Cit Y In D...mentioning

confidence: 90%

“…Progress in our understanding of the role of GluA1 and GluA1‐containing AMPARs in the brain will undoubtedly shed light on novel therapeutic strategies for the treatment of dementia and age‐related cognitive disorders like AD. For example, activation of M1 receptors promotes the membrane insertion of GluA1 through phosphorylation of S845, a critical site for AMPAR trafficking to the synapse 71 . In that animal model, M1 receptor activation reversed learning and memory impairments through the modulation of GluA1 trafficking.…”

Section: Role Of Glua1 In Aberrant Synaptic Plasticity In Disease Statesmentioning

confidence: 96%

Emerging role of AMPA receptor subunit GluA1 in synaptic plasticity: Implications for Alzheimer's disease

Yuan

et al. 2020

Cell Proliferation

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It is well established that GluA1 mediated synaptic plasticity plays a central role in the early development of AD. The complex cellular and molecular mechanisms that enable GluA1‐related synaptic regulation remain to fully understood. Particularly, understanding the mechanisms that disrupt GluA1 related synaptic plasticity is central to the development of disease‐modifying therapies which are sorely needed as the incidence of AD rises. We surmise that the published evidence establishes deficits in synaptic plasticity as a central factor of AD aetiology. We additionally highlight potential therapeutic strategies for the treatment of AD, and we delve into the roles of GluA1 in learning and memory. Particularly, we review the current understanding of the molecular interactions that confer the actions of this ubiquitous excitatory receptor subunit including post‐translational modification and accessory protein recruitment of the GluA1 subunit. These are proposed to regulate receptor trafficking, recycling, channel conductance and synaptic transmission and plasticity.

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“…However, although compounds showed some success in animal models ( Bretin et al., 2017 ; Giralt et al., 2017 ; Lauterborn et al., 2016 ), they have had low clinical success ( Bernard et al., 2019 ; Trzepacz et al., 2013 ; Wezenberg et al., 2007 ). Owing to a lack of chemical diversity among the Ampakines, alternative strategies for AMPAR-based treatment are being considered ( Chang et al., 2012 ; Hao et al., 2015 ; Lee et al., 2016 ; Zhao et al., 2019 ). Our results provide a basis for pharmacological manipulation of AMPAR acetylation as a potential therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

et al. 2020

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Summary In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

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M1 Muscarinic Receptor Activation Rescues β-Amyloid-Induced Cognitive Impairment through AMPA Receptor GluA1 Subunit

Cited by 11 publications

References 44 publications

Electro-Acupuncture Improve the Early Pattern Separation in Alzheimer’s Disease Mice via Basal Forebrain-Hippocampus Cholinergic Neural Circuit

Electro-Acupuncture Improve the Early Pattern Separation in Alzheimer’s Disease Mice via Basal Forebrain-Hippocampus Cholinergic Neural Circuit

Emerging role of AMPA receptor subunit GluA1 in synaptic plasticity: Implications for Alzheimer's disease

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

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