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Astrocytes and the TGF-β1 Pathway in the Healthy and Diseased Brain: a Double-Edged Sword

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Abstract

Transforming growth factor betas (TGF-βs) are known as multifunctional growth factors that participate in the regulation of key events of development, disease, and tissue repair. In the brain, TGF-β1 has been widely recognized as an injury-related cytokine, particularly associated with astrocyte scar formation in response to brain injury. In the last decade, however, evidence has indicated that in addition to its role in brain injury, TGF-β1 might be a crucial regulator of cell survival and differentiation, brain homeostasis, angiogenesis, memory formation, and neuronal plasticity. In this review, we will discuss the emerging scenario of TGF-β1 as a key regulator of astrocyte differentiation and function and the implications of TGF-β1 as a novel mediator of cellular interactions in the central nervous system. First, we will discuss the cellular and molecular basis underlying the effect of TGF-β on astrocyte generation and its impact on angiogenesis and blood-brain barrier function. Then, we will focus on the role of astrocytes in the development and remodeling of synapses and the role of TGF-β1 as a new mediator of these events. Furthermore, we present seminal data that contributed to the emerging concept that astrocyte dysfunction might be associated with neurodegenerative diseases, with a special focus on Alzheimer’s disease, and discuss the pros and cons of TGF-β signaling deficits in these processes. Finally, we argue that understanding how astrocytic signals, such as TGF-β1, regulate brain function might offer new insights into human learning, memory, and cognition, and ultimately, this understanding may provide new targets for the treatment of neurological diseases.

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Abbreviations

AD:

Alzheimer’s disease

AβO:

Aβ oligomers

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

BLBP:

Brain lipid binding protein

BMP:

Bone morphogenetic protein

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

CNS:

Central nervous system

CR3:

C3 receptor

CREB:

AMP responsive element binding transcription factor

ECM:

Extracellular matrix

ECs:

Endothelial cells

FGFb:

Fibroblast growth factor beta

GDFs:

Growth and differentiation factors

GFAP:

Glial fibrillary acidic protein

GGT:

γ-Glutamyl transferase

GLAST:

Astrocyte-specific glutamate-aspartate transporter

Gpr124:

G protein-coupled endothelial receptor 124

HHT2:

Hereditary hemorrhagic telangiectasia type 2

i.c.v.:

Intracerebroventricular injection

IL-6:

Interleukin 6

JNK:

c-jun-N-terminal kinase

LAP:

Latency-associated peptide

LIF:

Leukemia inhibitory factor

LPS:

Lipopolysaccharide

LTD:

Long-term depression

LTP:

Long-term potentiation

MAPK:

Mitogen-activated protein kinase

NPCs:

Neural progenitor cells

PAI-1:

Plasminogen activator inhibitor-1

PAP:

Perisynaptic astrocyte processes

PD:

Parkinson’s disease

PDGF-b:

Platelet-derived growth factor beta

PI3K:

Phosphatidylinositol-3 kinase

PNVP:

Perivascular neural plexus

PNS:

Peripheral nervous system

RG:

Radial glia cells

RGCs:

Retinal ganglion cells

SASP:

Senescence-associated secretory phenotype

SVZ:

Subventricular zone

TGF-β1:

Transforming growth factor beta one

TβR1:

TGF-β type I receptor

TβR2:

TGF-β type II receptor

TβR3:

TGF-β type III receptor

TNF-α:

Tumor necrosis factor alpha

TSP:

Thrombospondin

VEGF-A:

Vascular endothelial growth factor A

VZ:

Ventricular zone

ZO-1:

Zonula occludens-1

β–Gal:

β-galactosidase

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Acknowledgments

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Departamento de Ciência e Tecnologia do Ministério da Saúde (Decit), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). This manuscript was edited by the American Journal Experts (AJE).

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  1. Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil

    Luan Pereira Diniz, Isadora Matias, Michele Siqueira, Joice Stipursky & Flávia Carvalho Alcantara Gomes

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Diniz, L.P., Matias, I., Siqueira, M. et al. Astrocytes and the TGF-β1 Pathway in the Healthy and Diseased Brain: a Double-Edged Sword. Mol Neurobiol 56, 4653–4679 (2019). https://doi.org/10.1007/s12035-018-1396-y

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