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      TGF-β Signaling: A Therapeutic Target to Reinstate Regenerative Plasticity in Vascular Dementia?


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          Vascular dementia (VaD) is the second leading form of memory loss after Alzheimer's disease (AD). Currently, there is no cure available. The etiology, pathophysiology and clinical manifestations of VaD are extremely heterogeneous, but the impaired cerebral blood flow (CBF) represents a common denominator of VaD. The latter might be the result of atherosclerosis, amyloid angiopathy, microbleeding and micro-strokes, together causing blood-brain barrier (BBB) dysfunction and vessel leakage, collectively originating from the consequence of hypertension, one of the main risk factors for VaD. At the histopathological level, VaD displays abnormal vascular remodeling, endothelial cell death, string vessel formation, pericyte responses, fibrosis, astrogliosis, sclerosis, microglia activation, neuroinflammation, demyelination, white matter lesions, deprivation of synapses and neuronal loss. The transforming growth factor (TGF) β has been identified as one of the key molecular factors involved in the aforementioned various pathological aspects. Thus, targeting TGF-β signaling in the brain might be a promising therapeutic strategy to mitigate vascular pathology and improve cognitive functions in patients with VaD. This review revisits the recent understanding of the role of TGF-β in VaD and associated pathological hallmarks. It further explores the potential to modulate certain aspects of VaD pathology by targeting TGF-β signaling.

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          Making sense of latent TGFbeta activation.

          TGFbeta is secreted as part of a latent complex that is targeted to the extracellular matrix. A variety of molecules, 'TGFbeta activators,' release TGFbeta from its latent state. The unusual temporal discontinuity of TGFbeta synthesis and action and the panoply of TGFbeta effects contribute to the interest in TGF-beta. However, the logical connections between TGFbeta synthesis, storage and action are obscure. We consider the latent TGFbeta complex as an extracellular sensor in which the TGFbeta propeptide functions as the detector, latent-TGFbeta-binding protein (LTBP) functions as the localizer, and TGF-beta functions as the effector. Such a view provides a logical continuity for various aspects of TGFbeta biology and allows us to appreciate TGFbeta biology from a new perspective.
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            TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.

            Ligands of the transforming growth factor-beta (TGFbeta) superfamily of growth factors initiate signal transduction through a bewildering complexity of ligand-receptor interactions. Signalling then converges to nuclear accumulation of transcriptionally active SMAD complexes and gives rise to a plethora of specific functional responses in both embryos and adult organisms. Current research is focused on the mechanisms that regulate SMAD activity to evoke cell-type-specific and context-dependent transcriptional programmes. An equally important challenge is understanding the functional role of signal strength and duration. How are these quantitative aspects of the extracellular signal regulated? How are they then sensed and interpreted, and how do they affect responses?
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              Rejuvenation of regeneration in the aging central nervous system.

              Remyelination is a regenerative process in the central nervous system (CNS) that produces new myelin sheaths from adult stem cells. The decline in remyelination that occurs with advancing age poses a significant barrier to therapy in the CNS, particularly for long-term demyelinating diseases such as multiple sclerosis (MS). Here we show that remyelination of experimentally induced demyelination is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis. Restored remyelination in old animals involves recruitment to the repairing lesions of blood-derived monocytes from the young parabiotic partner, and preventing this recruitment partially inhibits rejuvenation of remyelination. These data suggest that enhanced remyelinating activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life. Copyright © 2012 Elsevier Inc. All rights reserved.

                Author and article information

                Aging Dis
                Aging Dis
                Aging and Disease
                JKL International LLC
                July 2020
                23 July 2020
                : 11
                : 4
                : 828-850
                [1-ad-11-4-828] 1Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.
                [2-ad-11-4-828] 2Faculty Recharge Programme, University Grants Commission (UGC-FRP), New Delhi, India.
                [3-ad-11-4-828] 3Molecular Gerontology Group, Department of Biochemistry, School of Life Sciences, Bharathidhasan University, Tiruchirappalli, Tamil Nadu, India.
                [4-ad-11-4-828] 4Institute of Molecular Regenerative Medicine, Salzburg, Paracelsus Medical University.
                [5-ad-11-4-828] 5Spinal Cord Injury and Tissue Regeneration Center, Salzburg, Paracelsus Medical University, Salzburg, Austria.
                [6-ad-11-4-828] 6Velvio GmbH, Regensburg, Germany.
                [7-ad-11-4-828] 7Austrian Cluster for Tissue Regeneration, Vienna, Austria
                Author notes
                [* ]Correspondence should be addressed to: Dr. Ludwig Aigner, Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria. Email: ludwig.aigner@ 123456pmu.ac.at .
                Copyright: © 2020 Kandasamy et al.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.



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