Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Qin, Xike; Wang, Yunling; Paudel, Hemant K.

doi:10.1074/jbc.m116.738849

Cited by 27 publications

(30 citation statements)

References 61 publications

(78 reference statements)

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“…More recently, EGR1 has also been implicated as a driving factor of AD neuropathology and cognitive decline, since hippocampal EGR1 inhibition was shown to reduce tau phosphorylation, lower Aβ pathology, and improve cognition in 3xTG-AD mice [ 183 ]. Since EGR1 inhibition was also shown to activate BACE1 activity [ 184 ], this calls for further studies into the role of (early life) modulation of EGR1 and its implication in cognitive impairment and AD neuropathology.…”

Section: Resultsmentioning

confidence: 99%

Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

et al. 2018

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BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder with a high prevalence among the elderly and a huge personal and societal impact. Recent epidemiological studies have indicated that the incidence and age of onset of sporadic AD can be modified by lifestyle factors such as education, exercise, and (early) stress exposure. Early life adversity is known to promote cognitive decline at a later age and to accelerate aging, which are both primary risk factors for AD. In rodent models, exposure to ‘negative’ or ‘positive’ early life experiences was recently found to modulate various measures of AD neuropathology, such as amyloid-beta levels and cognition at later ages. Although there is emerging interest in understanding whether experiences during early postnatal life also modulate AD risk in humans, the mechanisms and possible substrates underlying these long-lasting effects remain elusive.MethodsWe review literature and discuss the role of early life experiences in determining later age and AD-related processes from a brain and cognitive ‘reserve’ perspective. We focus on rodent studies and the identification of possible early determinants of later AD vulnerability or resilience in relation to early life adversity/enrichment.ResultsPotential substrates and mediators of early life experiences that may influence the development of AD pathology and cognitive decline are: programming of the hypothalamic–pituitary–adrenal axis, priming of the neuroinflammatory response, dendritic and synaptic complexity and function, overall brain plasticity, and proteins such as early growth response protein 1 (EGR1), activity regulated cytoskeleton-associated protein (Arc), and repressor element-1 silencing transcription factor (REST).ConclusionsWe conclude from these rodent studies that the early postnatal period is an important and sensitive phase that influences the vulnerability to develop AD pathology. Yet translational studies are required to investigate whether early life experiences also modify AD development in human studies, and whether similar molecular mediators can be identified in the sensitivity to develop AD in humans.

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Section: Resultsmentioning

confidence: 99%

Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

et al. 2018

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“…The overlap observed between the Aβ neurotoxicity pathway genes established in rodent cultures ( Killick et al, 2014 ) and the human CLU knockout neurons further supports the involvement of clusterin in Aβ-dependent neurodegeneration, and adds to the evidence suggesting this molecular cascade as a mechanism. Knockdown of EGR1 was previously found to prevent Aβ-induced toxicity and EGR1 has been previously reported to dysregulate key AD genes, including BACE and presenilin-2 ( Renbaum et al, 2003 ; Killick et al, 2014 ; Qin et al, 2016 ). Further investigation of these transcription factors that are dysregulated by Aβ and CLU in a human iPSC-derived model of AD may help to elucidate their role in Aβ-dependent neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Clusterin Is Required for β-Amyloid Toxicity in Human iPSC-Derived Neurons

et al. 2018

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Our understanding of the molecular processes underlying Alzheimer’s disease (AD) is still limited, hindering the development of effective treatments, and highlighting the need for human-specific models. Advances in identifying components of the amyloid cascade are progressing, including the role of the protein clusterin in mediating β-amyloid (Aβ) toxicity. Mutations in the clusterin gene (CLU), a major genetic AD risk factor, are known to have important roles in Aβ processing. Here we investigate how CLU mediates Aβ-driven neurodegeneration in human induced pluripotent stem cell (iPSC)-derived neurons. We generated a novel CLU-knockout iPSC line by CRISPR/Cas9-mediated gene editing to investigate Aβ-mediated neurodegeneration in cortical neurons differentiated from wild type and CLU knockout iPSCs. We measured response to Aβ using an imaging assay and measured changes in gene expression using qPCR and RNA sequencing. In wild type neurons imaging indicated that neuronal processes degenerate following treatment with Aβ25-35 peptides and Aβ1-42 oligomers, in a dose dependent manner, and that intracellular levels of clusterin are increased following Aβ treatment. However, in CLU knockout neurons Aβ exposure did not affect neurite length, suggesting that clusterin is an important component of the amyloid cascade. Transcriptomic data were analyzed to elucidate the pathways responsible for the altered response to Aβ in neurons with the CLU deletion. Four of the five genes previously identified as downstream to Aβ and Dickkopf-1 (DKK1) proteins in an Aβ-driven neurotoxic pathway in rodent cells were also dysregulated in human neurons with the CLU deletion. AD and lysosome pathways were the most significantly dysregulated pathways in the CLU knockout neurons, and pathways relating to cytoskeletal processes were most dysregulated in Aβ treated neurons. The absence of neurodegeneration in the CLU knockout neurons in response to Aβ compared to the wild type neurons supports the role of clusterin in Aβ-mediated AD pathogenesis.

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“…Recently, we have also found Egr‐1 up‐regulation induces β‐secretase 1 (BACE‐1) expression and promotes Aβ synthesis (Qin et al . ). Furthermore, we showed previously that Egr‐1 expression correlated with hyperphosphorylated tau (Lu et al .…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, we have recently found significantly reduced levels of Aβ and BACE‐1 in Egr‐1−/− mice, which are believed to cause amyloid pathology in AD (Qin et al . ). However, Egr‐1−/− mice lack late protein synthesis‐dependent LTP in the dentate gyrus leading to impaired long‐term spatial memory (Jones et al .…”

Section: Discussionmentioning

confidence: 97%

Early growth response‐1‐mediated down‐regulation of drebrin correlates with loss of dendritic spines

Cho

Macdonald

Shang

et al. 2017

Journal of Neurochemistry

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Post-synaptic dendritic spines are structurally composed of actin cytoskeleton, which undergoes dynamic morphological changes to accommodate incoming synaptic activity. Drebrin is an actin-binding protein highly expressed in dendritic spines that serves an important role in regulating spine morphology. Functionally, loss of drebrin directly correlates with deficits in learning and memory, as is the case observed in Alzheimer's disease. Despite these findings, the regulatory factor responsible for drebrin loss remains unclear. Here, we show that early growth response-1 (Egr-1), an inducible zinc finger transcription factor, down-regulates drebrin expression. Chromatin immunoprecipitation analyses identified Egr-1 binding sites upstream of the drebrin start site in neuronal cells. Over-expression of Egr-1 in vitro in primary hippocampal neurons or in vivo in homogenates prepared from the hippocampi of an inducible mouse model of Egr-1 show reduced drebrin mRNA and protein levels. Conversely, increased drebrin was detected in hippocampal samples isolated from Egr-1-deficient brain. These data demonstrate that Egr-1 interacts with the drebrin promoter and negatively regulates drebrin expression. Furthermore, immunocytochemical and Golgi staining analyses revealed reduced drebrin protein and dendritic spine density as well as reduced expression of synaptic markers in in vitro hippocampal neurons over-expressing Egr-1 and in vivo inducible mouse model of Egr-1. In contrast, increased drebrin expression correlated with increased dendritic spine density was detected in samples from Egr-1-deficient mice. These data provide evidence that Egr-1 is a novel regulator of drebrin expression, which is linked to changes in dendritic spine density.

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Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Cited by 27 publications

References 61 publications

Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

Clusterin Is Required for β-Amyloid Toxicity in Human iPSC-Derived Neurons

Early growth response‐1‐mediated down‐regulation of drebrin correlates with loss of dendritic spines

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