Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt–PCP–JNK pathway

Killick, Richard; Ribé, Elena M.; Al‐Shawi, Raya; Malik, Bilal; Hooper, Claudie; Fernandes, Cathy; Dobson, Richard; Nolan, Patrick M.; Lourdusamy, Anbarasu; Furney, Simon J.; Kuang, Lin; Breen, Gerome; Wroe, Richard; To, Alvina; Leroy, Karelle; Čaušević, Mirsada; Usardi, Alessia; Robinson, Martha; Noble, Wendy; Williamson, Richard A.; Lunnon, Katie; Kellie, Stuart; Reynolds, C. Hugh; Bazenet, Chantal; Hodges, Angela; Brion, Jean Pierre; Stephenson, John; Simons, Paul; Lovestone, Simon

doi:10.1038/mp.2012.163

Cited by 204 publications

(246 citation statements)

References 61 publications

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“…BACE-1 then may accelerate A␤ synthesis. Consistent with this idea, A␤ exposure induces expressions of Egr-1 and BACE-1 in neurons (21,34). In contrast to this hypothesis, we found that A␤42 exposure does not significantly promote amyloidogenic APP processing in rat hippocampal primary neurons (data not shown).…”

Section: Discussioncontrasting

confidence: 55%

“…Previous studies have shown that the Egr-1 level is up-regulated in AD brains (18 -21, 37). Furthermore, levels of both BACE-1 and Egr-1 are elevated in the brain during aging (22,38,39), hypoxia, brain injury, ischemia, and inflammation (13,14) and in AD mouse models (13,21,23). These observations together indicate that Egr-1 is an activator of BACE-1 in the CNS and suggest that Egr-1 plays role in the up-regulation of levels of BACE-1 and A␤ in AD brain.…”

Section: Discussionmentioning

confidence: 51%

“…Because BACE-1 catalyzes a committed step in A␤ synthesis and A␤ causes neurodegeneration in various in vitro and in vivo models (35), it was suggested that A␤ may lead to a vicious cycle of neurodegeneration by promoting its own synthesis (36). A␤ also induces Egr-1 expression in rat cortical neurons (21). Therefore, to test whether Egr-1 plays any role in this process, we exposed rat hippocampal primary neurons to oligomeric A␤42 and analyzed them.…”

Section: A␤42 Exposure Enhances Levels Of Egr-1 and Bace-1 In Rat Hipmentioning

confidence: 99%

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

Qin

Wang

Paudel

2016

Journal of Biological Chemistry

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Accumulation of amyloid-␤ peptide (A␤) in the brain is regarded as central to Alzheimer's disease (AD) pathogenesis. A␤ is generated by a sequential cleavage of amyloid precursor protein (APP) by ␤-secretase 1 (BACE-1) followed by ␥-secretase. BACE-1 cleavage of APP is the committed step in A␤ synthesis. Understanding the mechanism by which BACE-1 is activated leading to A␤ synthesis in the brain can provide better understanding of AD pathology and help to develop novel therapies. In this study, we found that the levels of A␤ and BACE-1 are significantly reduced in the brains of mice lacking transcription factor early growth response 1 (Egr-1) when compared with the WT. We demonstrate that in COS-7 cells, Egr-1 binds to the BACE-1 promoter and activates BACE-1 transcription. In rat hippocampal primary neurons, overexpression of Egr-1 induces BACE-1 expression, activates BACE-1, promotes amyloidogenic APP processing, and enhances A␤ synthesis. In mouse hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and A␤ synthesis. Our data indicate that Egr-1 promotes A␤ synthesis via transcriptional activation of BACE-1 and suggest that Egr-1 plays role in activation of BACE-1 and acceleration of A␤ synthesis in AD brain. Egr-1 is a potential therapeutic target for AD.Progressive accumulation of A␤ 2 in the brain is strongly implicated in the pathogenesis of Alzheimer's disease (AD). A␤ is derived from amyloid precursor protein (APP) (1). In the amyloidogenic pathway, APP is cleaved by ␤-secretase (BACE-1) to generate a 99-amino acid membrane-bound protein C99 and soluble APP␤. C99 is further cleaved by ␥-secretase to produce the A␤ peptide. APP is also cleaved by ␣-secretase within the A␤ domain generating an 83-kDa protein C83. Subsequent cleavage of C83 by ␥-secretase generates a nontoxic short peptide P3 containing the C-terminal region of A␤.BACE-1 cleavage of APP is the rate-limiting step in A␤ production. BACE-1 is regarded as the essential enzyme in the A␤ synthesis in the brain (1).A number of studies have shown that the level of BACE-1 protein is significantly up-regulated in AD brain (2-6). It has been suggested that the up-regulation of BACE-1 initiates and/or accelerates A␤ synthesis and promotes AD pathogenesis (1). Determining the mechanism by which BACE-1 is activated in AD brain can provide better understanding of AD pathology and help develop therapies against AD. However, what activates BACE-1 in AD brain is not known. Interestingly, in rat brain, BACE-1 level is elevated following experimental traumatic brain injury (7), transient cerebral ischemia (8), and following occlusion of the middle cerebral artery (9). Oxidative stress induces BACE-1 expression in mouse brains (10) and vascular smooth and HEK-293 cells (11,12). Thus, several cellular events triggered by vascular insults elevate BACE-1 levels in the brain. It has been suggested that the biochemical pathway that is activated by vascular injuries may be involved in up-regulating BAC...

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 51%

Section: A␤42 Exposure Enhances Levels Of Egr-1 and Bace-1 In Rat Hipmentioning

confidence: 99%

See 1 more Smart Citation

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

Qin

Wang

Paudel

2016

Journal of Biological Chemistry

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“…Expressed in the bovine endometrium (24,88), DKK1 can bind to LRP5/6 and, in the presence of the transmembrane protein KREMEN, cause its internalization and destruction and thereby prevent formation of the WNT-FZD-LRP5/6 complex (86,89,90). In addition, DKK1 can activate the planar cell polarity pathway (91)(92)(93). Addition of DKK1 blocks the inhibitory actions of AMBMP on development (87).…”

Section: Dickkopf 1 and Regulation Of Wnt Signalingmentioning

confidence: 99%

Maternal embryokines that regulate development of the bovine preimplantation embryo

Hansen¹,

Denicol²,

Dobbs³

2014

Turk J Vet Anim Sci

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The zygote contains within its genome and epigenome the program to direct development through the embryonic, fetal, and postnatal periods. The execution of that program is dependent on the embryo's nongenetic inheritance from the oocyte and sperm (1,2) as well as on the environment in which development proceeds. Variation in the maternal environment can affect the ability of the preimplantation embryo to establish pregnancy. In cattle, the focus of this review, competence of the preimplantation embryo for growth and survival can be affected by maternal parity (3), lactational status (4), and circulating concentrations of progesterone (5). Moreover, patterns of gene expression in the endometrium are associated with survival of an embryo transferred to the uterus in the next ovulatory cycle (6,7).Development of the bovine embryo to the blastocyst in the absence of maternal signals (i.e. through in vitro production procedures) results in embryos with aberrant gene expression (8,9), lipid content (10,11), DNA methylation (12), and, as shown in the Table, reduced competence to establish pregnancy after transfer into recipients (13-17). Additionally, an increased proportion of embryos produced in vitro have developmental abnormalities that lead to increased neonatal death losses (18-20). Some of the problems with the in vitro-produced embryo could result from selection of incompetent oocytes or inadequate oocyte maturation. However, the importance of the maternal environment during development is indicated by observations that transfer of in vitro-produced embryos to the oviduct after fertilization limits some of the abnormalities associated with in vitro production (9,21).One function of the reproductive tract is to secrete bioactive molecules that regulate the embryo, oviduct, or endometrium. Genes for 115 ligands expressed in the endometrium had the corresponding receptor gene expressed by the embryo (22). Regulatory molecules produced by the oviduct and endometrium, which include hormones, growth factors, and cytokines, are referred to as embryokines when they function to regulate embryonic growth and development (23).It is likely that some of the variation in the ability of the reproductive tract to support embryonic development represents variation in secretion of embryokines. Indeed, several genes that were overexpressed in the endometrium of cows that subsequently became pregnant after embryo transfer as compared to cows that did not establish pregnancy are potential embryokines. These include NGF,

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“…It can bind a variety of ligands, giving great diversity of role for clusterin in cellular activities (Calero et al 2005). Clusterin has also been proposed to act as a chaperone molecule involved in the regulation of extracellular protein folding (Nuutinen et al 2009;Wyatt et al 2009), has been shown to be a target for β-amyloid neurotoxicity pathways (Killick et al 2012) and can also influence the formation of extracellular B-amyloid aggregates (Narayan et al 2012). In addition, there is strong evidence that clusterin can have a protective role during oxidative stress (Calero et al 2005;Carnevali et al 2006), ER stress-mediated apoptosis (Wang et al 2013) and may function by facilitating the clearance of misfolded proteins (Poon et al 2002;Wyatt et al 2011).…”

Section: Discussionmentioning

confidence: 99%

The chaperone protein clusterin may serve as a cerebrospinal fluid biomarker for chronic spinal cord disorders in the dog

Shafie

McLaughlin

Burchmore

et al. 2014

Cell Stress and Chaperones

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Chronic spinal cord dysfunction occurs in dogs as a consequence of diverse aetiologies, including long-standing spinal cord compression and insidious neurodegenerative conditions. One such neurodegenerative condition is canine degenerative myelopathy (DM), which clinically is a challenge to differentiate from other chronic spinal cord conditions. Although the clinical diagnosis of DM can be strengthened by the identification of the Sod1 mutations that are observed in affected dogs, genetic analysis alone is insufficient to provide a definitive diagnosis. There is a requirement to identify biomarkers that can differentiate conditions with a similar clinical presentation, thus facilitating patient diagnostic and management strategies. A comparison of the cerebrospinal fluid (CSF) protein gel electrophoresis profile between idiopathic epilepsy (IE) and DM identified a protein band that was more prominent in DM. This band was subsequently found to contain a multifunctional protein clusterin (apolipoprotein J) that is protective against endoplasmic reticulum (ER) stress-mediated apoptosis, oxidative stress, and also serves as an extracellular chaperone influencing protein aggregation. Western blot analysis of CSF clusterin confirmed elevated levels in DM compared to IE (p < 0.05). Analysis of spinal cord tissue from DM and control material found that clusterin expression was evident in neurons and that the clusterin mRNA levels from tissue extracts were elevated in DM compared to the control. The plasma clusterin levels was comparable between these groups. However, a comparison of clusterin CSF levels in a number of neurological conditions found that clusterin was elevated in both DM and chronic intervertebral disc disease (cIVDD) but not in meningoencephalitis and IE. These findings indicate that clusterin may potentially serve as a marker for chronic spinal cord disease in the dog; however, additional markers are required to differentiate DM from a concurrent condition such as cIVDD.

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Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt–PCP–JNK pathway

Cited by 204 publications

References 61 publications

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

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

Maternal embryokines that regulate development of the bovine preimplantation embryo

The chaperone protein clusterin may serve as a cerebrospinal fluid biomarker for chronic spinal cord disorders in the dog

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