Modulation of the MAPKs pathways affects Aβ-induced cognitive deficits in Alzheimer’s disease via activation of α7nAChR

Chang, Ke-Wei; Zong, Hang-Fan; Rizvi, Mohammad Yasir; Ma, Kai; Zhai, Wanying; Wang, Meng; Yang, Weina; Ji, Shengfeng; Qian, Yi‐Hua

doi:10.1016/j.nlm.2019.107154

Cited by 17 publications

(13 citation statements)

References 62 publications

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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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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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“…Besides, the content of phosphorylated and non-phosphorylated NMDAR subunits in the hippocampus of AD patients are reduced (Sze et al, 2001). Consistently, in SAMP8 mice or AD models injected with Aβ 25-35 or Aβ 1-42 , the expression of NMDAR1, NMDAR2A and NMDAR2B were decreased markedly in the hippocampus or cortex (K. W. Chang et al, 2020; K. Wang et al, 2018; Xu et al, 2016). Moreover, it has been demonstrated that ketamine, a noncompetitive NMDAR antagonist, could ameliorate the impaired learning and memory of developing mice induced by repetitive mechanical stress, and the mechanism may be associated with the increased hippocampal BDNF expression (C. H. Chang, Su, & Gean, 2018; Peng, Zhang, Wang, Ren, & Zhang, 2011).…”

Section: Discussionmentioning

confidence: 64%

Impaired learning and memory ability induced by a bilaterally hippocampal injection of streptozotocin in mice: involved with the adaptive changes of synaptic plasticity

Chen

Gao

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability and loss of self-sufficiency.ObjectiveTo establish an AD mice model, investigate the behavioral performance, and explore the potential mechanism.MethodsStreptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL /6 mice to establish the AD model. Behavioral changes (anhedonia and despair, balance and motor coordination, locomotion, and learning and memory) were examined and the serum concentrations of insulin and nesfatin-1 were measured by ELISA. The activation of hippocampal microglia was assessed by immunohistochemistry and the protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the prefrontal cortex (PFC) was detected via western blotting.ResultsThe STZ model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-β-catenin/β-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3β (ser9)/GSK-3β were reduced in the hippocampus.ConclusionA bilateral hippocampal microinjection of STZ could successfully duplicate an AD mice model, as indicated by the impaired learning and memory and the alternated synaptic plasticity, together with the hyperactive inflammatory response in the hippocampus and the imbalanced abundance of serum insulin and nesfatin-1. Apart from these, the mechanism might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC.Graphical abstract

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“…Besides, the content of phosphorylated and non-phosphorylated NMDAR subunits in the hippocampus of AD patients are reduced (Sze et al, 2001). Consistently, in SAMP8 mice or AD models injected with Aβ 25−35 or Aβ 1−42 , the expression of NMDAR1, NMDAR2A, and NMDAR2B were decreased markedly in the hippocampus or cortex (Xu et al, 2016;Wang K. et al, 2018;Chang et al, 2020). Moreover, it has been demonstrated that ketamine, a non-competitive NMDAR antagonist, could ameliorate the impaired learning and memory of developing mice induced by repetitive mechanical stress, and the mechanism may be associated with the increased hippocampal BDNF expression (Peng et al, 2011;Chang et al, 2018).…”

Section: Discussionmentioning

confidence: 90%

Impaired Learning and Memory Ability Induced by a Bilaterally Hippocampal Injection of Streptozotocin in Mice: Involved With the Adaptive Changes of Synaptic Plasticity

Chen

Gao

et al. 2021

Front. Aging Neurosci.

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Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability, and loss of self-sufficiency.Objective: To establish an AD-like mice model, investigate the behavioral performance, and explore the potential mechanism.Methods: Streptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL/6 mice, and the behavioral performance was observed. The serum concentrations of insulin and nesfatin-1 were measured by ELISA, and the activation of hippocampal microglia and astrocytes was assessed by immunohistochemistry. The protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the pre-frontal cortex (PFC) was detected via western blotting.Results: The STZ-microinjected model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice, together with an increase abundance of Aβ1−42 and Tau in the hippocampus and PFC. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-β-catenin/β-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3β (ser9)/GSK-3β were reduced in the hippocampus.Conclusion: A bilateral hippocampal microinjection of STZ could induce not only AD-like behavioral performance in mice, but also adaptive changes of synaptic plasticity against neuroinflammatory and endocrinal injuries. The underlying mechanisms might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC.

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Modulation of the MAPKs pathways affects Aβ-induced cognitive deficits in Alzheimer’s disease via activation of α7nAChR

Cited by 17 publications

References 62 publications

The Toxicity and Polymorphism of β-Amyloid Oligomers

The Toxicity and Polymorphism of β-Amyloid Oligomers

Impaired learning and memory ability induced by a bilaterally hippocampal injection of streptozotocin in mice: involved with the adaptive changes of synaptic plasticity

Impaired Learning and Memory Ability Induced by a Bilaterally Hippocampal Injection of Streptozotocin in Mice: Involved With the Adaptive Changes of Synaptic Plasticity

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