TGF-β Signaling: A Therapeutic Target to Reinstate Regenerative Plasticity in Vascular Dementia? - PubMed (original) (raw)

Review

. 2020 Jul 23;11(4):828-850.

doi: 10.14336/AD.2020.0222. eCollection 2020 Jul.

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Review

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

Mahesh Kandasamy et al. Aging Dis. 2020.

Abstract

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.

Keywords: BBB; TGF-β; endothelial cells; hippocampus; neural regeneration; oxidative stress; pericytes; vascular dementia.

Copyright: © 2020 Kandasamy et al.

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Figures

Figure 1.

Figure 1.

An overview of Vascular Dementia. The figure summarizes the possible biological and lifestyle risk factors, various forms of VaD, pathological hallmarks of VaD and indicates cognitive deficit as the final outcome of the disease.

Figure 2.

Figure 2.

TGF-β signaling in health and disease. Schematic representation of the TGF-β mediated Smad signaling through the TGF-β receptors. TGF-β binds to TGF-β receptor II, which induces the activation of TGF-β receptor I and activates the phosphorylation of Smad2/3 in the cytoplasm. The activated Smad2/3 binds to Smad4 in the cytoplasm and mobilize into the nucleus where they act as a transcription factor. This leads to various cell-type dependent responses essential for the tissue homoeostasis and various physiological functions. Dysregulation of the TGF-β pathway leads to abnormal cellular events and pathological hallmarks that are all part of the VaD pathology.

Figure 3.

Figure 3.

The intact neurovascular unit and breakdown of the neurovascular unit in VaD. Illustrations of the intact neurovascular unit that typically contains normal blood cells, endothelial cells, basement membrane ensheathed by pericytes and end feet of astrocytes in the brain. The figure also represents the breakdown of the neurovascular unit resulting from the BBB disruption, the crucial pathological hallmarks of VaD such as endothelial cell death and drift of pericyte. The activation of immune cells interaction between the activated microglia and peripheral blood cells leading to the release of TGF-β and breakdown of exosomes and release of macrovesicles in the brain of subjects with VaD.

Figure 4.

Figure 4.

TGF-β and its involvement in neuroinflammation and neurogenesis in the control brain in the context of VaD. Illustration of the regulation of adult neurogenesis by TGF-β at the level of neural stem cell (NSC) self-renewal, transformation of neuroblasts and neuronal differentiation. The intact blood vessel, astrogenesis through astrocyte precursor cell (APS) and oligodendrogenesis from oligodendrocyte precursor cells (OPC) and resident microglial cells are indicated. In the parallel side, the figure indicates the aberrant regulation of adult neurogenesis, activated astrogliosis, microglial activation, accumulation of amyloid β, formation of string vessel, demyelination, neurodegeneration resulting from neuroinflammation mediated abnormal levels of TGF- β in VaD.

Figure 5.

Figure 5.

A proposed mechanism for TGF-β activation in the VaD. The figure represents the proposed hypothesis that interaction between neuroblasts and activated microglial cells might lead to the production of the inactive form of the TGF-β attached with latent transforming growth factor-β binding protein (LTBP) through latency-associated peptide (LAP). The inactive form of TGF-β has generally been stored in the extracellular matrix (ECM). Vascular damage upon mitochondrial defects, release of free radical and acidification of the local microenvironment might be underlying mechanisms of the pathological activation and release of TGF-β in VaD.

Figure 6.

Figure 6.

Possible strategies to inactivate TGF-β signaling and expected outcomes in VaD. Illustration of possible ways to inhibit aberrant TGF-β signaling pathways. The activities of TGF-β and TGF-β receptors can be neutralized using various recombinant antibodies or their translation can be blocked using specific set of antisense oligonucleotides. Different synthetic molecules that can inhibit the phosphorylation of the TGF-β RII and Smad2/3 are also indicated. The blockade of pathogenic TGF-β signaling has been expected to mitigate the cognitive deficits through inhibition of various neuropathogenic events and promotion of neuroregenerative plasticity in VaD.

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References

    1. Cerejeira J, Lagarto L, Mukaetova-Ladinska EB (2012). Behavioral and psychological symptoms of dementia. Front Neurol, 3:73. - PMC - PubMed
    1. O'Brien JT, Thomas A (2015). Vascular dementia. Lancet, 386:1698-1706. - PubMed
    1. Collaborators GBDD (2019). Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 18:88-106. - PMC - PubMed
    1. Rizzi L, Rosset I, Roriz-Cruz M (2014). Global epidemiology of dementia: Alzheimer's and vascular types. Biomed Res Int, 2014:908915. - PMC - PubMed
    1. Podcasy JL, Epperson CN (2016). Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci, 18:437-446. - PMC - PubMed

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