Transcriptional regulation and its misregulation in Alzheimer’s disease

Chen, Xiao Fen; Zhang, Yunwu; Xu, Huaxi; Bu, Guojun

doi:10.1186/1756-6606-6-44

Cited by 58 publications

(48 citation statements)

References 130 publications

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“…Thus, the increased NF-κB activation in post-mortem AD brain could either be a protective response or a trigger for neurodegeneration and apoptosis, and at least one reason for this uncertainty lies in the fact that NF-κB activation leads to both upregulation of pro-survival and pro-apoptotic genes or pro-oxidant and antioxidant genes [52]. Another important issue in the NF-κB and AD connection is the regulation of amyloid beta homeostasis through transcriptional upregulation of various related enzymes and proteins especially APP and BACE1 [106]. The type 1 integral protein APP is coded by a gene located in chromosome 21and undergoes alternative splicing to generate several isoforms of the protein of which the one with 695 amino acids is present in the brain [107].…”

Section: Nf-κb and Alzheimer's Diseasementioning

confidence: 99%

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection

Kaur¹,

Banerjee²,

Bir³

et al. 2015

CTMC

101

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Oxidative stress and inflammatory response are important elements of Alzheimer's disease (AD) pathogenesis, but the role of redox signaling cascade and its cross-talk with inflammatory mediators have not been elucidated in details in this disorder. The review summarizes the facts about redox-signaling cascade in the cells operating through an array of kinases, phosphatases and transcription factors and their downstream components. The biology of NF-κB and its activation by reactive oxygen species (ROS) and proinflammatory cytokines in the pathogenesis of AD have been specially highlighted citing evidence both from post-mortem studies in AD brain and experimental research in animal or cell-based models of AD. The possibility of identifying new disease-modifying drugs for AD targeting NF-κBsignaling cascade has been discussed in the end.

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Section: Nf-κb and Alzheimer's Diseasementioning

confidence: 99%

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection

Kaur¹,

Banerjee²,

Bir³

et al. 2015

CTMC

101

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“…Transcription factors such as Sp1, HIF1, YY1, NFќB are known to regulate BACE1 at transcriptional level . As stabilization of BACE1 by ORP150 occurs at protein level, we investigated whether ORP150 also regulates BACE1 gene transcription.…”

Section: Resultsmentioning

confidence: 99%

ORP150‐CHIP chaperone antagonism control BACE1‐mediated amyloid processing

Chanana

Pati

2018

J of Cellular Biochemistry

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BACE1, a key protein involved in Alzheimer's progression, initiates Aβ42 generation that induce senile plaques in brain. However, the role of chaperone synergy or antagonism on BACE1-mediated amyloid processing is unknown. We have discovered that BACE1 as well as Aβ42 are antagonistically controlled by ER chaperone ORP150 and cellular chaperone CHIP. We have shown ORP150 as a chaperone interacts with and stabilizes BACE1 at post-translational level. Furthermore, ORP150 enhances BACE1-mediated amyloid processing thus masking CHIP-mediated BACE1 degradation. Conversely, siORP150 reversed the chaperone function of ORP150 resulting in BACE1 degradation. ORP150 and CHIP demonstrate antagonism under normal and stress conditions wherein they inversely regulate each other thus affecting BACE1 level. In conclusion, we have uncovered for the first time a phenomenon of chaperone antagonism on BACE1-mediated Aβ42 generation. Future strategy would require both suppression of ORP150 as well as activation of E3-ligase activity of CHIP that might prevent Aβ42 in Alzheimer's disease.

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“…For example, nuclear factor‐kappa B (NF‐κB) signaling plays an important role in gene regulation and is implicated in inflammation . Recently, many reports have shown that NF‐κB also regulates BACE1 transcription . Additionally, many natural products exhibit neuroprotective effects via multiple molecular mechanisms .…”

Section: Discussionmentioning

confidence: 99%

Licoflavonol Reduces Aβ Secretion by Increasing BACE1 Phosphorylation to Facilitate BACE1 Degradation

Chun

Yong

et al. 2019

Molecular Nutrition Food Res

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Scope In the previous study, Glycyrrhiza uralensis Fisch extract (GUE) inhibited Aβ secretion by inhibiting β‐site APP‐cleaving enzyme 1 (BACE1) transcription, and the active compounds semilicoisoflavone B (SB) and licoflavonol (LF) inhibited Aβ secretion. SB corresponds to the same mechanism as GUE, but LF has a different mechanism. In this study, the mechanism underlying inhibition of Aβ by LF is investigated. Methods and results The effects of LF on Aβ, sAPPα, and sAPPβ secretion are evaluated by ELISA, and the effect of LF on BACE1 expression is detected by western blotting. It is found that the effect of LF on Aβ secretion is due to promotion of BACE1 protein degradation, and that the effect of LF on Aβ and BACE1 expression is attenuated after cotreatment with the lysosome inhibitor chloroquine. In a subsequent mechanistic study, it is found that LF increases BACE1 phosphorylation to increase its interactions with ADP ribosylation factor‐binding proteins 1 and 3 (GGA1 and GGA3, respectively) and eventually facilitate BACE1 delivery to lysosomes for degradation. Conclusion This study is the first to demonstrate that the BACE1 phosphorylation inducer LF can modulate BACE1 trafficking and lead to facilitating degradation of BACE1, eventually decreasing Aβ secretion.

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Transcriptional regulation and its misregulation in Alzheimer’s disease

Cited by 58 publications

References 130 publications

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection

ORP150‐CHIP chaperone antagonism control BACE1‐mediated amyloid processing

Licoflavonol Reduces Aβ Secretion by Increasing BACE1 Phosphorylation to Facilitate BACE1 Degradation

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Transcriptional regulation and its misregulation in Alzheimer’s disease

Cited by 58 publications

References 130 publications

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer&#39;s Disease: The NF-&#954;B Connection

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer&#39;s Disease: The NF-&#954;B Connection

ORP150‐CHIP chaperone antagonism control BACE1‐mediated amyloid processing

Licoflavonol Reduces Aβ Secretion by Increasing BACE1 Phosphorylation to Facilitate BACE1 Degradation

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Product

Resources

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Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection