In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases

Bonneh‐Barkay, Dafna; Wang, Guoji; Starkey, Adam; Hamilton, Ronald L.; Wiley, Clayton A.

doi:10.1186/1742-2094-7-34

Cited by 241 publications

(244 citation statements)

References 20 publications

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“…The biomarkers investigated in this study are all found in CSF under normal physiological conditions, and the levels found correspond well with findings in previous studies [10,14,16,23]. Increased CSF levels of the biomarkers NFL, Ng, YKL-40, and VILIP-1 have been found in AD and correlate with neurodegeneration, suggesting a potential use as a surrogate marker of synaptic and neuronal loss [3,[22][23][24].…”

Section: Discussionsupporting

confidence: 89%

“…It is speculated that YKL-40 increases with neuroinflammation [14]. However, apart from AD, increased levels have been found in CSF after stroke, other neurological disorders, and normal aging [14][15][16][17]. This indicates that YKL-40 is more a general marker of neuroinflammation/astroglial activation secondary to many different etiologies, including Ab pathology [18].…”

Section: Introductionmentioning

confidence: 99%

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[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

Jensen

Portelius

Høgh

et al. 2017

Alzheimer's & Dementia

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Introduction: Physical exercise has gained increasing focus as a potential mean to maintain cognitive function in patients with Alzheimer's disease (AD). Alongside the markers of specific AD pathology (amyloid b and tau), other pathologies such as neuronal damage and synaptic loss have been proposed as markers of the disease. Here, we study the effect of physical exercise on biomarkers of neuronal and synaptic integrity. Methods: Cerebrospinal fluid (CSF) from 51 AD subjects who participated in the randomized controlled trial Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) was analyzed for the concentration of neurofilament light (NFL), neurogranin (Ng), visinin-like protein-1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Participants were subjected to either 16 weeks of moderate-to highintensity exercise (n 5 25) or treatment as usual (control group, n 5 26), and CSF was collected before and after intervention. Results: No significant differences in CSF concentrations of VILIP-1, YKL-40, NFL, and Ng were observed when comparing mean change from baseline between the exercise and control groups. Similarly, when classifying subjects based on their exercise levels, no significant changes were observed for the biomarkers in the control group compared with the high-exercise group (attending 80% of the exercise sessions with an intensity of 70% of maximum heart rate or above). Discussion: These results are not supportive of a modulatory effect of physical exercise on the selected biomarkers of neuronal and synaptic integrity in patients with AD.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

Jensen

Portelius

Høgh

et al. 2017

Alzheimer's & Dementia

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“…It has been shown that YKL-40 is expressed by activated microglial cells, which are the resident macrophages of the brain, in simian immunodeficiency viral Encephalitis-associated inflammation (23). However, a recent study showed that it is also secreted by reactive astrocytes (25). Because YKL-40 is expressed in GBM cells, which are of glial origin, it could be expected that YKL-40 is expressed by normal astrocytes either during development or in response to their activation.…”

Section: Discussionmentioning

confidence: 99%

“…Increased levels of YKL-40 have also been reported in CNS pathologies, including Alzheimer disease, HIV-associated dementia, and multiple sclerosis (22)(23)(24). Although YKL-40 is produced by activated microglia (23), it has recently been shown that it is also secreted by reactive astrocytes (25).…”

mentioning

confidence: 99%

A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40

Singh

Bhardwaj

Wilczynska

et al. 2011

Journal of Biological Chemistry

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Nuclear factor I-X3 (NFI-X3) is a newly identified splice variant of NFI-X that regulates expression of several astrocyte-specific markers, such as glial fibrillary acidic protein. Here, we identified a set of genes regulated by NFI-X3 that includes a gene encoding a secreted glycoprotein YKL-40. Although YKL-40 expression is up-regulated in glioblastoma multiforme, its regulation and functions in nontransformed cells of the central nervous system are widely unexplored. We find that expression of YKL-40 is activated during brain development and also differentiation of neural progenitors into astrocytes in vitro. Furthermore, YKL-40 is a migration factor for primary astrocytes, and its expression is controlled by both NFI-X3 and STAT3, which are known regulators of gliogenesis. Knockdown of NFI-X3 and STAT3 significantly reduced YKL-40 expression in astrocytes, whereas overexpression of NFI-X3 dramatically enhanced YKL-40 expression in glioma cells. Activation of STAT3 by oncostatin M induced YKL-40 expression in astrocytes, whereas expression of a dominant-negative STAT3 had a suppressive effect. Mechanistically, NFI-X3 and STAT3 form a complex that binds to weak regulatory elements in the YKL-40 promoter and activates transcription. We propose that NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression.Astrocytes, the most abundant CNS cells, are critical for many functions of normal and pathological brains (1, 2). Generation and differentiation of astrocytes from neural progenitors is controlled by activation of the JAK-STAT3, BMP-SMAD, and Notch-HES pathways in vivo (3, 4) and promoted by cytokines of the IL-6 family that activate STAT3 in vitro (5, 6). In addition to these pathways, evolutionarily conserved NFI 3 transcription factors, consisting of NFI-A, -B, -C, and -X, regulate astrocyte differentiation (7,8). NFIs are expressed in overlapping patterns during embryogenesis, with high expression levels of NFI-A, -B, and -X found in the developing neocortex (9, 10). Consequently, Nfia, Nfib, and Nfix knock-out mice show severe brain anatomical defects, including agenesis of corpus callosum (9, 10), whereas NPs from Nfix knock-out mice show defects in proliferation and migration (9, 10). NFI-A and -B control gliogenesis in chick embryonic spinal cord (7), whereas NFI-X and -C regulate the expression of late astrocyte markers during the differentiation of human NPs in vitro (7,8). Expression of NFI-A is induced by Notch signaling in NP and leads to the demethylation of astrocyte-specific genes (11), as well as down-regulation of Notch signaling via repression of Notch effector Hes1 (12). Each of the NFI transcripts undergoes alternative splicing, generating as many as nine different NFI splice variants (13), likely possessing distinctive functions. We have recently characterized a novel human NFI-X3 splice variant, which is a potent activator of gene expression in astrocytes (14). NFI-X3 contains a unique transcri...

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“…In the central nervous system (CNS), an elevated CHI3L1 was associated with glioblastoma and brain infarction [10], where the expression of CHI3L1 increased in the acute stage and then diminished at the chronic stage [3]. Recently, it has been reported that CHI3L1 is an astrocyte secreted protein in mice [11], and the proteomic analysis revealed a high secretion by mouse choroid plexus [21].…”

Section: Introductionmentioning

confidence: 99%

Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer’s disease

2011

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Previously, chitinase 3-like 1 (CHI3L1) protein level was increased in various inflammatory conditions and cancers. This study was aimed to evaluate the plasma CHI3L1 level as a potential prognostic biomarker for Alzheimer's disease (AD). Forty-nine patients with mild cognitive impairment (MCI), 61 patients with mild to severe AD, and 35 healthy elderly controls were recruited for this study. They were given a comprehensive neuropsychological test battery including a mini-mental status examination (MMSE), clinical dementia rating (CDR), and neuropsychiatric inventory (NPI). The CHI3L1 levels were measured using a specific enzyme-linked immunosorbent assay in the plasma and cerebrospinal fluid (CSF). A significant increase in the mean plasma level of CHI3L1 was found in early AD patients compared to control subjects and MCI patients. No significant difference was found between MCI patients and controls. There was a significant positive correlation between CHI3L1 levels and neuropsychological test scores such as CDR and NPI in MCI and early AD patients. Our results demonstrate that CHI3L1 plasma levels are elevated in early AD compared to control or MCI patients. Thus, CHI3L1 plasma levels may be useful as a biomarker, reflecting disease severity in AD patients.

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In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases

Cited by 241 publications

References 20 publications

[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

[P3–174]: EFFECT OF PHYSICAL EXERCISE ON MARKERS OF NEURONAL DYSFUNCTION IN CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER's DISEASE

A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40

Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer’s disease

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