Activation of α7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways

Chang, Ke-Wei; Zong, Hang-Fan; Ma, Kai; Zhai, Wanying; Yang, Weina; Hu, Xiaodan; Xu, Jin; Chen, Xinlin; Ji, Shengfeng; Qian, Yi‐Hua

doi:10.1016/j.neuint.2018.09.005

Cited by 36 publications

(13 citation statements)

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“…The α7 nAChR binds Aβ with high affinity [30] and internalizes Aβ into the endosomes/lysosomes and mitochondria [ 31 , 32 ]. Uptake of Aβ phosphorylates p38, induces apoptosis [31] and α7 nAChR agonists mitigate the Aβ-induced apoptosis in animal models [33] . Further studies are needed to elucidate the mechanistic link between receptor structure and Aβ binding with specifically designed studies incorporating genetic and pharmacological paradigms.…”

Section: Discussionmentioning

confidence: 99%

CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

et al. 2020

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Background Cholinergic neuronal loss is one of the hallmarks of AD related neurodegeneration; however, preclinical promise of α7 nAChR drugs failed to translate into humans. CHRFAM7A , a uniquely human fusion gene, is a negative regulator of α7 nAChR and was unaccounted for in preclinical models. Methods Molecular methods: Function of CHRFAM7A alleles was studied in vitro in two disease relevant phenotypic readouts: electrophysiology and Aβ uptake. Genome edited human induced pluripotent stem cells (iPSC) were used as a model system with the human context. Double blind pharmacogenetic study: We performed double-blind pharmacogenetic analysis on the effect of AChEI therapy based on CHRFAM7A carrier status in two paradigms: response to drug initiation and DMT effect. Mini Mental Status Examination (MMSE) was used as outcome measure. Change in MMSE score from baseline was compared by 2-tailed T-test. Longitudinal analysis of clinical outcome (MMSE) was performed using a fitted general linear model, based on an assumed autoregressive covariance structure. Model independent variables included age, sex, and medication regimen at the time of the first utilized outcome measure (AChEI alone or AChEI plus memantine), APOE4 carrier status (0, 1 or 2 alleles as categorical variables) and CHRFAM7A genotype. Findings The direct and inverted alleles have distinct phenotypes. Functional CHRFAM7A allele classifies the population as 25% non-carriers and 75% carriers. Induced pluripotent stem cell (iPSC) models α7 nAChR mediated Aβ neurotoxicity. Pharmacological readout translates into both first exposure ( p = 0.037) and disease modifying effect ( p = 0.0048) in two double blind pharmacogenetic studies. Interpretation CHRFAM7A accounts for the translational gap in cholinergic strategies in AD. Clinical trials not accounting for this uniquely human genetic factor may have rejected drug candidates that would benefit 25% of AD. Reanalyses of the completed trials using this pharmacogenetic paradigm may identify effective therapy. Funding:

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Section: Discussionmentioning

confidence: 99%

CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

et al. 2020

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“…However, some studies have found that α7nAChR had a neuroprotective effect. Activation of α7nAChR inhibited neuronal γ-secretase activity, and p38 or JNK activity, both of which contribute to the alleviation of Aβ burden and Aβ-induced memory deficits [ 53 , 54 , 55 ].…”

Section: The Neurotoxicological Mechanisms Of Aβosmentioning

confidence: 99%

The Toxicity and Polymorphism of β-Amyloid Oligomers

Huang

Liu

2020

IJMS

101

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It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.

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“…It has been proved that the deposition of Aβ in mitochondria and the promotion of ROS under the action of various metal ions are important features of AD during the development of AD [56][57][58]. The analysis of mouse models and autopsy of AD patients showed that mitochondrial dysfunction led to increased ROS, further exacerbating mitochondrial dysfunction, which further resulted in the deposition of Aβ.…”

Section: Discussionmentioning

confidence: 99%

Sodium Butyrate Protects N2a Cells against Aβ Toxicity In Vitro

Sun

Yuan

et al. 2020

Mediators of Inflammation

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Alzheimer’s disease (AD) is a common neurodegenerative disease. Aβ plays an important role in the pathogenesis of AD. Sodium butyrate (NaB) is a short-chain fatty acid salt that exerts neuroprotective effects such as anti-inflammatory, antioxidant, antiapoptotic, and cognitive improvement in central nervous system diseases. The aim of this study is to research the protective effects of NaB on neurons against Aβ toxicity and to uncover the underlying mechanisms. The results showed that 2 mM NaB had a significant improvement effect on Aβ-induced N2a cell injury, by increasing cell viability and reducing ROS to reduce injury. In addition, by acting on the GPR109A receptor, NaB regulates the expression of AD-related genes such as APP, NEP, and BDNF. Therefore, NaB protects N2a cells from Aβ-induced cell damage through activating GPR109A, which provides an innovative idea for the treatment of AD.

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Activation of α7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways

Cited by 36 publications

References 70 publications

CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

The Toxicity and Polymorphism of β-Amyloid Oligomers

Sodium Butyrate Protects N2a Cells against Aβ Toxicity In Vitro

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