TGF-β in the central nervous system: Potential roles in ischemic injury and neurodegenerative diseases

Pratt, Bruce M.; McPherson, John M.

doi:10.1016/s1359-6101(97)00018-x

Cited by 130 publications

(78 citation statements)

References 201 publications

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“…In this situation, it is possible that the local TGF␤2 concentration in the fluid around neurons increases to a level sufficient for induction of neuronal cell death in vivo when expression of TGF␤2 is enhanced. In AD brains, it has been reported that upregulated expression of TGF␤2 is seen not only in glial cells but also in neurons themselves (6,9,10,23,36,38). In agreement with this finding, we have recently found that toxic A␤42 upregulates expression of TGF␤2 (Y. Hashimoto, M. Nawa, and M. Matsuoka, unpublished), supporting the idea that expression of TGF␤2 is upregulated in AD brains.…”

Section: Discussionsupporting

confidence: 88%

Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

Hashimoto¹,

Chiba²,

Yamada

et al. 2005

Molecular and Cellular Biology

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APP, amyloid ␤ precursor protein, is linked to the onset of Alzheimer's disease (AD). We have here found that transforming growth factor ␤2 (TGF␤2), but not TGF␤1, binds to APP. The binding affinity of TGF␤2 to APP is lower than the binding affinity of TGF␤2 to the TGF␤ receptor. On binding to APP, TGF␤2 activates an APP-mediated death pathway via heterotrimeric G protein G o , c-Jun N-terminal kinase, NADPH oxidase, and caspase 3 and/or related caspases. Overall degrees of TGF␤2-induced death are larger in cells expressing a familial AD-related mutant APP than in those expressing wild-type APP. Consequently, superphysiological concentrations of TGF␤2 induce neuronal death in primary cortical neurons, whose one allele of the APP gene is knocked in with the V642I mutation. Combined with the finding indicated by several earlier reports that both neural and glial expression of TGF␤2 was upregulated in AD brains, it is speculated that TGF␤2 may contribute to the development of AD-related neuronal cell death.

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Section: Discussionsupporting

confidence: 88%

Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

Hashimoto¹,

Chiba²,

Yamada

et al. 2005

Molecular and Cellular Biology

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“…Earlier studies have suggested that autocrine or paracrine secretions may play a role in the proliferation, survival and differentiation of developing granule neurons (Gao et al, 1991;Mumm et al, 1996;Ueki et al, 2003;Wu et al, 2003). Although various experimental paradigms have indicated regulatory roles for the neurotrophin BDNF in these events (Lin et al, 1998;Borghesani et al, 2002) and other cytokines (Tao et al, 1997;Unsicker and Strelau, 2000;Pratt and McPherson, 1997;Alder et al, 1999;Angley et al, 2003), little is known about the identity of the intrinsic and environmental signals that maintain the equilibrium between neuronal birth, maturation and death. The appearance and differentiation of cerebellar and hippocampal granule neurons overlap only transiently: cerebellar granule cells enter a post-mitotic state at P7-14, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Three separate genes encode three isoforms of TGFβ: TGFβ1 (normally restricted to the choroid plexus); and the neuron-and glia-expressed isoforms TGFβ2 and TGFβ3 Pratt and McPherson, 1997). TGFβ1 and TGFβ3 have been implicated in neuroprotection, while neurotrophic functions have been ascribed to TGFβ2 and TGFβ3 (Finch et al, 1993;Böttner et al, 2000;Pratt and McPherson, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…TGFβ1 and TGFβ3 have been implicated in neuroprotection, while neurotrophic functions have been ascribed to TGFβ2 and TGFβ3 (Finch et al, 1993;Böttner et al, 2000;Pratt and McPherson, 1997). The latter include stimulation (Mahanthappa and Schwarting, 1993) or inhibition (Constam et al, 1994) of neurogenesis, or both (Kane et al, 1996), as well as the regulation of neuronal differentiation (Ishihara et al, 1994;Abe et al, 1996;Cameron et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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SMAD pathway mediation of BDNF and TGFβ2 regulation of proliferation and differentiation of hippocampal granule neurons

Sousa

et al. 2005

Development

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Hippocampal granule cells self-renew throughout life, whereas their cerebellar counterparts become post-mitotic during early postnatal development, suggesting that locally acting, tissue-specific factors may regulate the proliferative potential of each cell type. Confirming this, we show that conditioned medium from hippocampal cells (CMHippocampus)stimulates proliferation in cerebellar cultures and, vice versa, that mitosis in hippocampal cells is inhibited by CMCerebellum. The anti-proliferative effects of CMCerebellum were accompanied by increased expression of the cyclin-dependent kinase inhibitors p21 and p27, as well as markers of neuronal maturity/differentiation. CMCerebellumwas found to contain peptide-like factors with distinct anti-proliferative/differentiating and neuroprotective activities with differing chromatographic properties. Preadsorption of CMCerebellumwith antisera against candidate cytokines showed that TGFβ2 and BDNF could account for the major part of the anti-proliferative and pro-differentiating activities, an interpretation strengthened by studies involving treatment with purified TGFβ2 and BDNF. Interference with signaling pathways downstream of TGFβ and BDNF using dominant-negative forms of their respective receptors (TGFβ2-RII and TRKB) or of dominant-negative forms of SMAD3 and co-SMAD4 negated the anti-proliferative/differentiating actions of CMCerebellum. Treatment with CMCerebellum caused nuclear translocation of SMAD2 and SMAD4, and also transactivated a TGFβ2-responsive gene. BDNF actions were shown to depend on activation of ERK1/2 and to converge on the SMAD signaling cascade, possibly after stimulation of TGFβ2 synthesis/secretion. In conclusion, our results show that the regulation of hippocampal cell fate in vitro is regulated through an interplay between the actions of BDNF and TGFβ.

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“…Activated microglia can express receptors and the cognate ligands for both proinflammatory, e.g., interleukin-1 (IL-1) (73,179,217,240,259,278), 259,295), IL-12 (11,31,272,337), IL-16 (320), IL-23 (198), and tumor necrosis factor alpha (TNF-␣) (67,179,217,240,259,295), and antiinflammatory, e.g., transforming growth factor ␤ (TGF ␤) (88,292) and 211,377), classes of cytokines (Tables 1 and 2). The role of these cytokines in CNS infections is discussed more fully later in this review, but it is important to note that although microglia possess receptors for and can be activated by alpha, beta, and gamma interferons (IFN-␣, IFN-␤, and IFN-␥), it appears that microglia are incapable of generating appreciable quantities of these critical activating cytokines.…”

Section: Activated Microgliamentioning

confidence: 99%

Role of Microglia in Central Nervous System Infections

et al. 2004

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The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed

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TGF-β in the central nervous system: Potential roles in ischemic injury and neurodegenerative diseases

Cited by 130 publications

References 201 publications

Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

SMAD pathway mediation of BDNF and TGFβ2 regulation of proliferation and differentiation of hippocampal granule neurons

Role of Microglia in Central Nervous System Infections

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