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Cited by 27Alzheimer's disease research and treatmentsConnective Tissue Growth Factor ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index; 1 of the 48 sources its claims cite were checked for support.

Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia

Open access
Yang, Cheng-Ning, Wu, Min-Fang, Liu, Chung-Chih, Jung, Wei-Hung, Chang, Yu-Chin, Lee, Wang-Pao, Shiao, Young-Ji, Wu, Chia-Lin, Liou, Horng-Huei, Lin, Sze-Kwan, Chan, Chih-Chiang·2017·Human Molecular Genetics
DOI 10.1093/hmg/ddx278
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Abstract

Impaired clearance of amyloid-β peptide (Aβ) leads to abnormal extracellular accumulation of this neurotoxic protein that drives neurodegeneration in sporadic Alzheimer's disease (AD). Connective tissue growth factor (CTGF/CCN2) expression is elevated in plaque-surrounding astrocytes in AD patients. However, the role of CTGF in AD pathogenesis remains unclear. Here we characterized the neuroprotective activity of CTGF. We found that CTGF facilitated Aβ uptake and subsequent degradation within primary glia and neuroblastoma cells. CTGF enhanced extracellular Aβ degradation via membrane-bound matrix metalloproteinase-14 (MMP14) in glia and extracellular MMP13 in neurons. In the brain of a Drosophila AD model, glial-expression of CTGF reduced Aβ deposits, improved locomotor function, and rescued memory deficits. Neuroprotective potential of CTGF against Aβ42-induced photoreceptor degeneration was disrupted through silencing MMPs. Therefore, CTGF may represent a node for potential AD therapeutics as it intervenes in glia-neuron communication via specific MMPs to alleviate Aβ neurotoxicity in the central nervous system.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

CTGF is induced in glia, not neurons, by soluble Aβ and promotes Aβ clearance through cell-type-specific MMPs—MMP-14 in glia and MMP-13 in neurons. In a Drosophila Aβ42 model, neuronal or glial CTGF expression reduces Aβ deposits and vacuolization and rescues locomotor and olfactory memory deficits, with protection requiring MMPs.

Key findings

  • In APP/PS1 mouse cortex, CTGF levels were higher at 4, 8, and 10 months than in age-matched controls; CTGF co-labeled with NeuN and GFAP but not Iba1. Upon soluble Aβ, CTGF was induced in mixed glia but not SH-SY5Y cells, and rCTGF reduced soluble Aβ-induced caspase-3 activation.
  • rCTGF (0.1 or 0.5 µg/ml) reduced remaining soluble Aβ in media time- and dose-dependently in mixed glia and SH-SY5Y cells, increased intracellular Aβ uptake, and enhanced subsequent degradation; chloroquine reduced neuronal lysosomal Aβ degradation.
  • Glial extracellular Aβ degradation required MMP-14: rCTGF upregulated MMP-13 and MMP-14 mRNA but only MMP-14 protein; batimastat abolished clearance and an MMP-14 blocking antibody reduced it. Neuronal degradation required MMP-13: rCTGF upregulated MMP-13, batimastat abolished clearance, shMMP-13 clones blocked it, and recombinant MMP-13 directly degraded soluble Aβ.
  • In Aβ42 flies, neuronal CTGF reduced 4G8-positive puncta, SDS-soluble and formic acid-soluble Aβ42, and vacuolization; it restored climbing at 7 and 21 days and olfactory learning at 21 days. Glial repo-CTGF also reduced rhabdomere loss, 4G8 puncta, Thio-S aggregates, and vacuolization and rescued learning. Knockdown of dMMP-1 or dMMP-2 disrupted CTGF protection in photoreceptors.

Methods

  • Primary rat mixed glia from postnatal day 1 cortex, primary microglia, and human SH-SY5Y neuroblastoma cells were treated with synthetic Aβ1-42, recombinant CTGF, batimastat, or chloroquine; assays included Western blot, ELISA, qPCR, confocal imaging, pulse-chase, and conditioned-medium experiments.
  • Drosophila models used UAS-Aβ42, UAS-CTGF, repo-CTGF, and dMMP-1/dMMP-2 RNAi lines with pan-neuronal elav-GAL4, eye-specific GMR-GAL4, or glia-specific repo expression; readouts included 4G8 and Thioflavin-S staining, phalloidin/Na+/K+ ATPase staining, vacuole counts, Aβ42 ELISA, climbing, and Pavlovian olfactory associative learning.
  • Data are expressed as mean ± SEM and analyzed by one-way ANOVA followed by Fisher’s LSD test, with p < 0.05 considered significant.

Limitations

  • Stated: whether stimulating CTGF activity protects in an APP/PS1 mouse AD model, or whether high CTGF levels associate with better prognosis in human AD patients, awaits investigation; mechanisms by which CTGF differentially activates MMP-13 in neurons and MMP-14 in glia need further elucidation; whether CTGF protects against other neurotoxic insults or neurodegenerative diseases requires further study; endogenous CTGF is not sufficient to overcome the long course of continuous Aβ burden.
  • Evident from the text: the in vivo evidence is from Drosophila, with mammalian data from cultured rat glia and human neuroblastoma cells, so no mammalian in vivo AD model or human interventional data are presented; CTGF effects were tested using recombinant protein or ectopic/overexpression, and some supporting observations are reported as “data not shown” (e.g., neuronal CTGF mRNA and dMMP overexpression).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/hmg/ddx278

Cites

56 of 56 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

1 of 48 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    Pulse-chase experiment shows enhanced efficiency of intracellular Ab degradation at a later time point in rCTGF-treated SH-SY5Y cells.

    “In addition, the pulse-chase experiment showed enhanced efficiency of intracellular Ab degradation at a later time point (Fig. 3E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Upon rCTGF incubation, mRNA of both MMP-13 and -14 is significantly upregulated in mixed glial cells compared to non-treated control.

    “Upon rCTGF incubation, the mRNA of both MMP-13 and -14 was significantly upregulated, compared to non-treated control (Fig. 2A, and Supplementary Material, Fig. S3A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Colocalization of intracellular Ab with LAMP1 is increased upon rCTGF treatment in SH-SY5Y cells.

    “Notably, we observed an increased colocalization of intracellular Ab with lysosomal-associated membrane protein (LAMP) 1 upon rCTGF treatment (Fig. 3C).”
    Quote in the paperSubstantial claim
  • Findingown data

    The level of CTGF in the media increases in soluble Ab-treated mixed glial cells.

    “The level of CTGF in the media also increased in sAb-treated mixed glial cells (Supplementary Material, Fig. S1G).”
    Quote in the paperSubstantial claim
  • Findingown data

    Lysosomal inhibitor chloroquine significantly reduces intracellular Ab degradation in SH-SY5Y cells.

    “The lysosomal inhibitor chloroquine significantly reduced intracellular Ab degradation (Fig. 3F), further supporting lysosomal degradation of Ab.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 24
  • It may state two separate claims as one. 32

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Some MMPs may play an important role in degrading soluble Ab, such as secreted MMP-2 and MMP-9 that generate C-terminally truncated Ab fragments and membrane-type MMP-14 that degrades both soluble and fibrillary Ab.

    “Increasing in vitro evidence indicates that some MMPs may play an important role in degrading soluble Ab (sAb), such as secreted MMP-2 and MMP-9 that generate C-terminally truncated Ab fragments and membrane-type MMP-14 that degrades both soluble and fibrillary Ab (29)(30)(31)(32).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [29] Backstrom, 1996, Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40), J. Neurosci source

      The Results and Figure 6 show that activated MMP-9 cleaves soluble Aβ1–40, producing C-terminally truncated fragments including Aβ1–34. The citations are grouped at the end of the sentence, and this paper does not establish the attributed Aβ-degrading activities of MMP-2 or MMP-14. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [30] Deb, 2003, Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes, Brain Res source
    • cites [31] Hernandez-Guillamon, 2015, Sequential Amyloid-beta Degradation by the Matrix Metalloproteases MMP-2 and MMP-9, J. Biol. Chem source

  • It may state two separate claims as one.

    Findingown data

    Protein level of MMP-14 increases upon rCTGF treatment in mixed glial cells, while MMP-13 does not.

    “We then checked protein levels by Western blot, and found an increase only in MMP-14 upon rCTGF treatment (Fig. 2B and C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In the brain of a Drosophila AD model, glial-expression of CTGF reduced Ab deposits, improved locomotor function, and rescued memory deficits.

    “In the brain of a Drosophila AD model, glial-expression of CTGF reduced Ab deposits, improved locomotor function, and rescued memory deficits.”
    • Also stated in: § Glia-secreted CTGF prevents Ab-induced toxicity in AD fly · plain
      “The Ab-induced defect in olfactory associative learning was also rescued by glial expression of CTGF (Fig. 7F), similar to our findings following CTGF expression in neurons (Fig. 5G).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    CTGF enhances extracellular Ab degradation via membrane-bound MMP14 in glia and extracellular MMP13 in neurons.

    “CTGF enhanced extracellular Ab degradation via membrane-bound matrix metalloproteinase-14 (MMP14) in glia and extracellular MMP13 in neurons.”
    • Also stated in: § CTGF-mediated extracellular degradation of soluble Ab is dependent on matrix metalloproteinase 14 in glia · plain
      “Thus, CTGF stimulates glial cells to produce MMP-14 for extracellular clearance of sAb.”
    • Also stated in: § CTGF-mediated extracellular degradation of soluble Ab is dependent on neuronal matrix metalloproteinase 13 · plain
      “Thus, CTGF stimulates neuronal cells to generate MMP-13 for extracellular clearance of sAb.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Recombinant CTGF promotes glial uptake and/or extracellular degradation of soluble Ab.

    “Thus, rCTGF promoted glial uptake and/or extracellular degradation of sAb.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    CTGF promotes both uptake and subsequent degradation of Ab in glial cells.

    “Taken together, CTGF promotes both the uptake and subsequent degradation of Ab in glial cells.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Neuronal cells fail to produce CTGF in response to Ab but respond to rCTGF by clearing intracellular Ab.

    “Although neuronal cells failed to produce CTGF in response to Ab, they responded to rCTGF by clearing intracellular Ab.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Intracellular Ab level is significantly lower at 1 h after soluble Ab incubation in rCTGF-pretreated mixed glial cells, but no difference is observed at other time points compared to vehicle control.

    “Intracellular Ab level was significantly lower at 1 h after sAb incubation, but no difference was observed at other time points compared to vehicle-treated control (Fig. 1F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    CTGF is induced in glial cells, but not in SH-SY5Y cells, upon soluble Ab supplementation.

    “We then examined CTGF expression upon supplementing soluble Ab to SH-SY5Y cells or mixed glial cells from rat cortex (postnatal day 1), and found by Western blot that CTGF was induced in glial cells, but not in SH-SY5Y cells (Supplementary Material, Fig. S1E and F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Recombinant CTGF enhances not only soluble Ab uptake but also subsequent degradation in neuronal cells.

    “Thus, similar to its effect on glial cells, rCTGF enhances not only sAb uptake but also subsequent degradation in neuronal cells.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Both neuronal- and glial-specific expression of CTGF significantly reduce Ab synaptotoxicity and ameliorate memory deficits in a fly model of AD.

    “We further tested the effects of CTGF in vivo, and found that both neuronal-and glial-specific expression of CTGF significantly reduced Ab synaptotoxicity and ameliorated memory deficits in a fly model of AD.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Neuronal expression of Ab results in significant decline in olfactory learning performance in 7-day-old flies, exacerbated in 21-day-old AD flies, and rescued to control levels by neuronal co-expression of CTGF.

    “In contrast, in 7-day-old flies, neuronal expression of Ab resulted in a significant decline in olfactory learning performance, which was exacerbated in 21-day-old AD flies and rescued to control levels by neuronal co-expression of CTGF (Fig. 5G).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Co-expression of CTGF in Ab42 flies restores locomotor dysfunction to levels comparable to controls, whereas CTGF alone has no effect on locomotor activity.

    “Co-expression of CTGF in Ab flies restored locomotor dysfunction to the levels comparable to those in the controls, whereas expression of CTGF alone had no effect on locomotor activity (Fig. 5F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Mixed glial cells, but not neuroblastoma cells, respond to soluble Ab stimulation by elevating levels of CTGF.

    “By examining both neuronal and glial cultures, we observed that mixed glial cells, but not neuroblastoma cells, responded to sAb stimulation by elevating the levels of CTGF.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Overexpression of dMMP-1 does not rescue Ab-induced neurodegeneration in the eye of the fly model of AD, and overexpression of dMMP-2 even aggravates eye morphology.

    “However, overexpression of dMMP-1 did not rescue Ab-induced neurodegeneration in the eye of the fly model of AD, and overexpression of dMMP-2 even aggravated the eye morphology (data not shown).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The two MMPs exhibited CTGF-dependent Ab-degrading activity, with MMP-13 acting in neurons and MMP-14 in glia.

    “In addition, we have shown that the two MMPs exhibited CTGFdependent Ab-degrading activity, with MMP-13 acting in neurons and MMP-14 in glia.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Knockdown of dMMP-1 or dMMP-2 disrupts protective effect of CTGF when Ab42 and CTGF are co-expressed, reducing numbers of rhabdomeres compared to Ab42 flies.

    “However, knockdown of dMMP-1 or dMMP-2 disrupted the protective effect of CTGF when Ab42 and CTGF were co-expressed, as we observed the reduction in the numbers of rhabdomeres as compared to Ab42 flies (Fig. 6C and D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Recombinant CTGF supplementation to culture medium of neuronal cells increases protein levels of CTGF without affecting its mRNA abundance.

    “Although neuronal expression of CTGF is not induced, rCTGF supplementation to the culture medium of neuronal cells increased the protein levels of CTGF without affecting its mRNA abundance (data not shown).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    CTGF increases levels of MMP-13 and MMP-14 proteins in neurons and glial cells, respectively.

    “Furthermore, CTGF increased levels of MMP-13 and MMP-14 proteins in neurons and glial cells, respectively.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Glial cells respond to nearly all types of central nervous system insults or neurodegenerative diseases, including AD, with reactive gliosis ranging from upregulation of gene transcription to enhanced secretion of matricellular proteins for remodeling of extracellular matrix surrounding neurons.

    “Glial cells respond to nearly all types of central nervous system (CNS) insults or neurodegenerative diseases, including AD.These glial responses, so called”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Bezzi, 2004, Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate, Nat. Neurosci source
    • cites [9] Verkhratsky, 2014, Glia in the pathogenesis of neurodegenerative diseases, Biochem. Soc. Trans source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Many signaling molecules secreted by reactive glia have been proposed to mediate neuron-glia interactions in AD pathogenesis.

    “Many signaling molecules secreted by reactive glia have been proposed to mediate neuron-glia interactions in AD pathogenesis (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Lian, 2016, Signaling pathways regulating neuron-glia interaction and their implications in Alzheimer's disease, J. Neurochem source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In a mouse AD model, CTGF expression in the brain is increased upon diabetic challenge.

    “In a mouse AD model, CTGF expression in the brain is increased upon diabetic challenge (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Zhao, 2005, Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology, Faseb J source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    CCN family proteins play a role in multiple processes including proliferation, apoptosis, and cell migration in non-CNS tissues and the nervous system.

    “The CCN (CYR61/CTGF/NOV) family proteins play a role in multiple processes including proliferation, apoptosis, and cell migration in non-CNS tissues and the nervous system (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Malik, 2015, Matricellular proteins of the Cyr61/CTGF/NOV (CCN) family and the nervous system, Front. Cell. Neurosci source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    CTGF is found in glial cells and cortical neurons of both rat and human brains.

    “Notably, CTGF is also found in glial cells and cortical neurons of both rat and human brains (16)(17)(18).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Kondo, 1999, Immunohistochemical localization of connective tissue growth factor in the rat central nervous system, Brain Res source
    • cites [17] Meeuwsen, 2003, Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli, Glia source
    • cites [18] Schwab, 2001, Differential cellular accumulation of connective tissue growth factor defines a subset of reactive astrocytes, invading fibroblasts, and endothelial cells following central nervous system injury in rats and humans, J. Neurotrauma source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Both neurons and glia can clear extracellular Ab through endocytosis for subsequent lysosomal degradation or secretion of amyloid-degrading enzymes for extracellular clearance.

    “We and others have shown that both neurons and glia can clear extracellular Ab through endocytosis for subsequent lysosomal degradation or secretion of amyloiddegrading enzymes for extracellular clearance (4,7).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Tarasoff-Conway, 2015, Clearance systems in the brain-implications for Alzheimer disease, Nat. Rev. Neurol source
    • cites [7] Yang, 2011, Mechanism mediating oligomeric Abeta clearance by naive primary microglia, Neurobiol. Dis source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Impairment of Ab clearance is the major cause of sporadic late-onset AD.

    “Recent evidence suggested that the impairment of Ab clearance was the major cause of sporadic late-onset AD (5)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Mawuenyega, 2010, Decreased clearance of CNS beta-amyloid in Alzheimer's disease, Science source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    CTGF is upregulated in glia upon acute brain injury such as stroke, spinal cord injury, or neurodegenerative diseases such as amyotrophic lateral sclerosis and AD.

    “It is further upregulated in glia upon acute brain injury such as stroke (19), spinal cord injury (20), or neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) (21) and AD (22).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Schwab, 2000, Connective tissue growth factor is expressed by a subset of reactive astrocytes in human cerebral infarction, Neuropathol. Appl. Neurobiol source
    • cites [20] Mokalled, 2016, Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish, Science source
    • cites [21] Spliet, 2003, Increased expression of connective tissue growth factor in amyotrophic lateral sclerosis human spinal cord, Acta Neuropathol source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In a healthy brain, Ab homeostasis is maintained by a balance between its production and clearance, whereas in AD brain overproduction and/or reduced clearance of Ab result in the formation of amyloid deposits.

    “In a healthy brain, Ab homeostasis is maintained by a balance between its production and clearance, whereas in AD brain overproduction and/or reduced clearance of Ab result in the formation of amyloid deposits (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Tarasoff-Conway, 2015, Clearance systems in the brain-implications for Alzheimer disease, Nat. Rev. Neurol source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Strong correlation is observed between the severity of cognitive impairment in AD and the levels of oligomeric rather than aggregated Ab in senile plaques.

    “Strong correlation is observed between the severity of cognitive impairment in AD and the levels of oligomeric rather than aggregated Ab in senile plaques (2,3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Hardy, 2002, The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics, Science source
    • cites [3] Viola, 2015, Amyloid beta oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis, Acta Neuropathol source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Impaired clearance of amyloid-beta peptide (Ab) leads to abnormal extracellular accumulation of this neurotoxic protein that drives neurodegeneration in sporadic Alzheimer's disease.

    “Recent evidence suggested that the impairment of Ab clearance was the major cause of sporadic late-onset AD (5)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Mawuenyega, 2010, Decreased clearance of CNS beta-amyloid in Alzheimer's disease, Science source

  • Probably not a substantial claim.

    Premisecitation

    Accumulation of Ab in the brain leads to progressive neuronal loss in Alzheimer's disease, the most common form of dementia.

    “The accumulation of amyloid-b peptide (Ab) in the brain leads to progressive neuronal loss in Alzheimer's disease (AD), the most common form of dementia (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Musiek, 2015, Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’, Nat. Neurosci source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    CTGF has been shown to induce expression of specific MMPs in several pathophysiological conditions, including MMP-2 in retinal neovascularization and diabetic nephropathy, MMP-2 and MMP-3 in tumor metastasis, and MMP-3 and MMP-13 in osteoarthritis.

    “CTGF has been shown to induce the expression of specific MMPs in several pathophysiological conditions, including MMP-2 in both retinal neovascularization (33) and diabetic nephropathy (34), MMP-2 and MMP-3 in tumor metastasis (35), and MMP-3 and MMP-13 in osteoarthritis (36).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Chintala, 2012, Connective tissue growth factor regulates retinal neovascularization through p53 protein-dependent transactivation of the matrix metalloproteinase (MMP)-2 gene, J. Biol. Chem source
    • cites [34] McLennan, 2004, Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1: implications for diabetic nephropathy, Endocrinology source
    • cites [35] Tsai, 2014, CTGF increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating miR-519d, Oncotarget source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    CTGF has been proposed as a tumor suppressor or potential therapeutic target for lung and ovarian cancers and fibrosis.

    “Therefore, it has been proposed as a tumor suppressor or potential therapeutic target for lung and ovarian cancers and fibrosis (13)(14)(15).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Kikuchi, 2007, Promoter hypermethylation contributes to frequent inactivation of a putative conditional tumor suppressor gene connective tissue growth factor in ovarian cancer, Cancer Res source
    • cites [14] Chen, 2007, Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer, PLoS One source
    • cites [15] Jun, 2011, Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets, Nat. Rev. Drug Discov source

  • It may state two separate claims as one.

    Interpretationreasoning

    CTGF may represent a node for potential AD therapeutics as it intervenes in glia-neuron communication via specific MMPs to alleviate Ab neurotoxicity in the central nervous system.

    “Therefore, CTGF may represent a node for potential AD therapeutics as it intervenes in glia-neuron communication via specific MMPs to alleviate Ab neurotoxicity in the central nervous system.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    Therapeutic approaches targeting Ab clearance may be beneficial for the treatment of AD.

    “suggesting that therapeutic approaches targeting Ab clearance may be beneficial for the treatment of AD (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Morrone, 2015, Interaction between therapeutic interventions for Alzheimer's disease and physiological Abeta clearance mechanisms, Front. Aging Neurosci source

  • It may state two separate claims as one.

    Premisecitation

    The fly model of AD displays many features of the disease, including Ab deposition in the brain, neuronal degeneration, locomotor dysfunction, and memory deficits.

    “The fly model of AD displays many features of the disease, including Ab deposition in the brain, neuronal degeneration, locomotor dysfunction, and memory deficits (37)(38)(39).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Crowther, 2006, A Drosophila model of Alzheimer's disease, Methods Enzymol source
    • cites [38] Iijima, 2004, Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease, Proc. Natl. Acad. Sci. U S A source
    • cites [39] Prussing, 2013, Drosophila melanogaster as a model organism for Alzheimer's disease, Mol. Neurodegener source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    MMPs are a large family of zinc-containing endoproteases whose role has been demonstrated in degrading extracellular matrix proteins and tissue remodeling.

    “Matrix metalloproteinases (MMPs) are a large family of zinccontaining endoproteases whose role has been demonstrated in degrading ECM proteins and tissue remodeling (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Page-McCaw, 2007, Matrix metalloproteinases and the regulation of tissue remodelling, Nat. Rev. Mol. Cell Biol source

  • It may state two separate claims as one.

    Interpretationreasoning

    Upon Ab challenge, glia produces CTGF to enhance clearance of Ab through MMPs, hence preventing neurotoxicity and improving memory function.

    “Therefore, we propose a mechanism wherein, upon Ab challenge, glia produces CTGF to enhance the clearance of Ab through the MMPs, hence preventing the neurotoxicity and improving memory function (Fig. 7F).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Integration of transfected plasmid DNA was confirmed by Western blot in the stable transfected cell lines.

    “Integration of transfected plasmid DNA was confirmed by Western blot.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    Impairment of Ab uptake and clearance by neurons, glia, and blood-brain-barrier endothelial cells may explain why the level of Ab is elevated and accumulates during AD progression.

    “Impairment of Ab uptake and clearance by neurons, glia, and blood-brain-barrier endothelial cells may explain why the level of Ab is elevated and accumulates during AD progression (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Tarasoff-Conway, 2015, Clearance systems in the brain-implications for Alzheimer disease, Nat. Rev. Neurol source

  • Probably not a substantial claim.

    Premisecitation

    There are only two MMPs in Drosophila, the secreted dMMP-1 and membrane-anchored dMMP-2.

    “There are only two MMPs in Drosophila, the secreted dMMP-1 and membrane-anchored dMMP-2 (32,48).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Liao, 2010, Degradation of soluble and fibrillar amyloid beta-protein by matrix metalloproteinase (MT1-MMP) in vitro, Biochemistry source
    • cites [48] Llano, 2002, Structural and enzymatic characterization of Drosophila Dm2-MMP, a membrane-bound matrix metalloproteinase with tissue-specific expression, J. Biol. Chem source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    CTGF can be internalized into cytosol by human mesangial cells and exert protective effect against diabetic nephropathy.

    “In support of this possibility, CTGF can be internalized into the cytosol by human mesangial cells and exert its protective effect against diabetic nephropathy (51).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Wahab, 2001, Uptake and intracellular transport of the connective tissue growth factor: a potential mode of action, Biochem. J source

  • It may state two separate claims as one.

    Interpretationown data

    CTGF exerts its protective effects by promoting Ab clearance, thus attenuating Ab-induced neurotoxicity in both cellular and animal models.

    “In this work, we show for the first time that CTGF exerts its protective effects by promoting Ab clearance, thus attenuating Ab-induced neurotoxicity in both cellular and animal models.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Protective effect of CTGF in photoreceptors is disrupted by silencing either of the dMMPs, suggesting these may be effectors for CTGF activity.

    “Our findings indicate that the protective effect of CTGF in photoreceptors is disrupted by silencing either of the dMMPs, suggesting that these may be the effectors for CTGF activity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    These MMPs function in several processes including neural development, tissue remodeling, and tumor progression.

    “These MMPs function in several processes including neural development, tissue remodeling, and tumor progression (24,49,54,55).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Page-McCaw, 2007, Matrix metalloproteinases and the regulation of tissue remodelling, Nat. Rev. Mol. Cell Biol source
    • cites [49] Llano, 2000, Dm1-MMP, a matrix metalloproteinase from Drosophila with a potential role in extracellular matrix remodeling during neural development, J. Biol. Chem source
    • cites [54] Beaucher, 2007, Metastatic ability of Drosophila tumors depends on MMP activity, Dev. Biol source

  • It may state two separate claims as one.

    Interpretationreasoning

    Endogenous CTGF is not sufficient to overcome the long course of continuous Ab burden, albeit enhanced expression of CTGF is found adjacent to amyloid plaques.

    “However, the endogenous CTGF is not sufficient to overcome the long course of continuous Ab burden, albeit enhanced expression of CTGF is found adjacent to amyloid plaques.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    TGF-beta is secreted by reactive glial cells upon Ab challenge, and TGF-beta enhances Ab clearance by microglia resulting in neuronal protection from Ab toxicity.

    “For example, TGF-b was secreted by reactive glial cells upon Ab challenge, and TGF-b enhanced Ab clearance by microglia resulting in neuronal protection from Ab toxicity (52,53).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Apelt, 2001, Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology, Brain Res source
    • cites [53] Wyss-Coray, 2001, TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice, Nat. Med source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Levels of CTGF also increase in traumatic brain injury and amyotrophic lateral sclerosis.

    “Moreover, levels of CTGF also increase in traumatic brain injury and amyotrophic lateral sclerosis (18,21).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Schwab, 2001, Differential cellular accumulation of connective tissue growth factor defines a subset of reactive astrocytes, invading fibroblasts, and endothelial cells following central nervous system injury in rats and humans, J. Neurotrauma source
    • cites [21] Spliet, 2003, Increased expression of connective tissue growth factor in amyotrophic lateral sclerosis human spinal cord, Acta Neuropathol source
48 of 48

  • The paper relies on this without support.

    No effective therapy for Alzheimer's disease is currently available.

    “Despite countless efforts to design therapeutic strategies for AD, no effective therapy is currently available.”

  • The paper relies on this without support.

    The Drosophila genome lacks an obvious CTGF homolog, making it a clean system to examine ectopic CTGF expression.

    “No obvious homolog of CTGF has been identified in the fly genome, making it a clean system to examine the neuroprotection of ectopic CTGF expression.”

  • The paper relies on this without support.

    Reactive gliosis is often found in close proximity to amyloid plaques and is positively correlated with the progression of Alzheimer's disease.

    “Reactive gliosis is often found in close proximity to amyloid plaques, and is in positive correlation with the progression of AD.”

  • The paper relies on this without support.

    Accumulation of misfolded/aggregated proteins in the central nervous system is common to several neurodegenerative diseases including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

    “As accumulation of misfolded/ aggregated proteins in the CNS is common to several neurodegenerative diseases including Parkinson's disease, Huntington's disease, and ALS, further studies are needed to examine whether activation of CTGF-degrading mechanisms may also protect neurons against the toxicity of other misfolded/aggregated proteins and subsequently decelerate the progression of these Neuro”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Glial CTGF is reported to worsen a photoreceptor measure despite a protective conclusion

    Minor

    Fewer rhabdomeres indicate greater photoreceptor degeneration, so the reported decrease relative to Ab42 flies conflicts with the conclusion that glial CTGF protects neurons from Ab-induced toxicity.

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1074/jbc.m006045200

    Info

    The cited work was retracted on 2019-01-25 (notice 10.1074/jbc.w118.007322), not before this paper was published (2017-07-14).

    Cited work 10.1074/jbc.m006045200 · retracted 2019-01-25 · notice 10.1074/jbc.w118.007322 · this paper published 2017-07-14

1 of 1

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1 retracted

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Metadata

Authors
Yang, C.-N., Wu, M.-F., Liu, C.-C., Jung, W.-H., Chang, Y.-C., Lee, W.-P., Shiao, Y.-J., Wu, C.-L., Liou, H.-H., Lin, S.-K., & Chan, C.-C.
Affiliations
  • National Taiwan University (TW)
  • Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
  • Chang Gung University (TW)
  • National Research Institute of Chinese Medicine (TW)
  • National Taiwan University Hospital (TW)
Corresponding author
Chan, Chih-Chiang
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2017-07-14
Volume
26
Issue
20
Pages
3909-3921
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddx278
OpenAlex
W2735112771
Cited by
27
References
56
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 8 · 2019: 2 · 2018: 1
FWCI
1.27
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Science and Technology of Taiwan (MOST 103-2320-B-002-025, 104-2321-B-002-069, 104-2311-B-002-017-MY3)
  • National Taiwan University (103R39012, 105R76273, and ERP-106R880401)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
connective tissue growth factor, amyloid-beta, Alzheimer's disease, neuroprotection, MMP-14, MMP-13, glia-neuron communication, astrocytes, amyloid-beta clearance, amyloid-beta 42, photoreceptor degeneration, memory impairment
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Brain, Disease Models, Animal, Drosophila, Humans, Neuroglia, Neurons, Peptide Fragments, Amyloid beta-Peptides, Neuroprotective Agents, Neurotoxicity Syndromes, Animals, Genetically Modified, Mice, Rats, Matrix Metalloproteinase 14, Connective Tissue Growth Factor, Plaque, Amyloid

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

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