Transforming growth factor-β1 in the cerebrospinal fluid of patients with distinct neurodegenerative diseases

Masuda, Tomoyuki; Itoh, Junko; Koide, Takuya; Takei, Yosuke; Ishii, Kazuhiro; Tamaoka, Akira

doi:10.1016/j.jocn.2016.09.018

Cited by 14 publications

(6 citation statements)

References 14 publications

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“…These methods, furthermore, would not be specific to astrocyte release. Of note, it has been shown that in the cerebrospinal fluid of AD postmortem patients, there was a trend of increase in TGF‐β2 (Vawter et al ., ) while discordant data have been published for TGF‐β1 (Blasko et al ., ; Masuda et al ., ); (iv) we have not looked at the receptors, either on glia or on neurons, that may sense TGF‐β changes as this was not the scope of the work, although this would provide further insight into the mechanisms described; and (v) given that this work focused on cultured cells, we do not have any behavioral correlates on the effect of TGF‐β release from astrocytes.…”

Section: Discussionmentioning

confidence: 97%

TGF‐β2 and TGF‐β3 from cultured β‐amyloid‐treated or 3xTg‐AD‐derived astrocytes may mediate astrocyte–neuron communication

Tapella

Cerruti

Biocotino

et al. 2018

Eur J of Neuroscience

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Astrocytes participate in the development and resolution of neuroinflammation in numerous ways, including the release of cytokines and growth factors. Among many, astrocytes release transforming growth factors beta (TGF-β) TGF-β1, TGF-β2 and TGF-β3. TGF-β1 is the most studied isoform, while production and release of TGF-β2 and TGF-β3 by astrocytes have been poorly characterized. Here, we report that purified cultures of hippocampal astrocytes produce mainly TGF-β3 followed by TGF-β2 and TGF-β1. Furthermore, astrocytes release principally the active form of TGF-β3 over the other two. Changes in release of TGF-β were sensitive to the calcineurin (CaN) inhibitor FK506. Starvation had no effect on TGF-β1 and TGF-β3 while TGF-β2 mRNA was significantly up-regulated in a CaN-dependent manner. We further investigated production and release of astroglial TGF-β in Alzheimer's disease-related conditions. Oligomeric β-amyloid (Aβ) down-regulated TGF-β1, while up-regulating TGF-β2 and TGF-β3, in a CaN-dependent manner. In cultured hippocampal astrocytes from 3xTg-AD mice, TGF-β2 and TGF-β3, but not TGF-β1, were up-regulated, and this was CaN-independent. In hippocampal tissues from symptomatic 3xTg-AD mice, TGF-β2 was up-regulated with respect to control mice. Finally, treatment with recombinant TGF-βs showed that TGF-β2 and TGF-β3 significantly reduced PSD95 protein in cultured hippocampal neurons, and this effect was paralleled by conditioned media from Aβ-treated astrocytes or from astrocytes from 3xTg-AD mice. Taken together, our data suggest that TGF-β2 and TGF-β3 are produced by astrocytes in a CaN-dependent manner and should be investigated further in the context of astrocyte-mediated neurodegeneration.

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Section: Discussionmentioning

confidence: 97%

TGF‐β2 and TGF‐β3 from cultured β‐amyloid‐treated or 3xTg‐AD‐derived astrocytes may mediate astrocyte–neuron communication

Tapella

Cerruti

Biocotino

et al. 2018

Eur J of Neuroscience

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“…A recent study has confirmed the existence of a negative correlation between TGFB1 and TGFB3 levels and ALS severity; this study postulated that high levels of TGFB in the serum might represent a compensatory mechanism to counteract the pronounced systemic immune response typical of the late stage of the disease, by inducing T cells to differentiate into non regulatory phenotypes [ 48 ]. Even if the increase in plasma TGFB1 levels has been confirmed also in mutSOD1 transgenic mice [ 49 ], whether TGFB1 plasma levels are biomarkers of ALS or not is still an open question; in fact, other studies fail to detect the changes of TGFB1 levels in patient CSF compared to healthy controls [ 50 ], or between fast and slow progressing ALS patients analyzed both at early and late stage of disease [ 49 ].…”

Section: Tgfb Plasma Levels In Als Patientsmentioning

confidence: 99%

Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis

Galbiati

Crippa

Rusmini

et al. 2020

IJMS

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Transforming growth factor beta (TGFB) is a pleiotropic cytokine known to be dysregulated in many neurodegenerative disorders and particularly in amyotrophic lateral sclerosis (ALS). This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons but also the surrounding glial cells, and the target skeletal muscle fibers. Here, we analyze the multiple roles of TGFB in these cell types, and how TGFB signaling is altered in ALS tissues. Data reported support a crucial involvement of TGFB in the etiology and progression of ALS, leading us to hypothesize that an imbalance of TGFB signaling, diminished at the pre-symptomatic stage and then increased with time, could be linked to ALS progression. A reduced stimulation of the TGFB pathway at the beginning of disease blocks its neuroprotective effects and promotes glutamate excitotoxicity. At later disease stages, the persistent activation of the TGFB pathway promotes an excessive microglial activation and strengthens muscular dysfunction. The therapeutic potential of TGFB is discussed, in order to foster new approaches to treat ALS.

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“…However, we have found that 3 of the ve PD-VPs that interact with it appear upregulated/signicantly-increased in blood (APP [84] and SERPINE1 [85]) or CSF (TGFB1 [86]) of PD patients. The other two PD-VPs are neuroprotective for PD (HGF [87] and TIMP1 [88]).…”

Section: Discussionmentioning

confidence: 77%

Cascading from SARS-CoV-2 to Parkinson's Disease through Protein-Protein Interactions

Estrada

2021

Preprint

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Background : Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD some hypothesis have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients in general and for the PD cases reported in particular. Given the importance of this potential connection we present here a molecular-level mechanism that explain well these findings and will serve to explore the potential CNS damage in COVID-19 patients. Methods : A model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Results : We found 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. Conclusions : The molecular-level mechanism presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.

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Transforming growth factor-β1 in the cerebrospinal fluid of patients with distinct neurodegenerative diseases

Cited by 14 publications

References 14 publications

TGF‐β2 and TGF‐β3 from cultured β‐amyloid‐treated or 3xTg‐AD‐derived astrocytes may mediate astrocyte–neuron communication

TGF‐β2 and TGF‐β3 from cultured β‐amyloid‐treated or 3xTg‐AD‐derived astrocytes may mediate astrocyte–neuron communication

Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis

Cascading from SARS-CoV-2 to Parkinson's Disease through Protein-Protein Interactions

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