Dysfunction of Cerebrovascular Endothelial Cells: Prelude to Vascular Dementia

Wang, Feixue; Cao, Yu; Ma, Lina; Peng, Hui; Rausch, Wolf Dieter; Li, Hao

doi:10.3389/fnagi.2018.00376

Cited by 123 publications

(126 citation statements)

References 347 publications

(387 reference statements)

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“…Astroglial-specific production of TGF-β in aged transgenic mice expressing the amyloid beta precursor protein (APP) minimizes dystrophic neurites and rescues neurodegeneration [51,216]. However, prolonged activation of microglia and thereby induced presence of an increased amount of TGF-β in the brain is linked to the synaptic loss in AD and VaD [155,[217][218][219][220]. Also of relevance, the clinical signature of various forms of dementia is most likely linked to the synaptic dysfunctions rather than neurodegeneration [221,222].…”

Section: Loss Of Synapses and Neurodegeneration In Vad And The Role Omentioning

confidence: 99%

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

et al. 2020

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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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Section: Loss Of Synapses and Neurodegeneration In Vad And The Role Omentioning

confidence: 99%

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

et al. 2020

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“…ЭК микрососудов мозга в наибольшей степени страдают от гипоперфузии, в результате которой нарушается целостность ГЭБ. Дисфункция ЭК и гипоперфузия взаимодополняют друг друга, образуя порочный круг, хотя молекулярные механизмы такого взаимовлияния очень слабо изучены [113]. Основными факторами риска развития СД являются старение, ожирение, гипертония, диабет, гиперхолестеринемия, гипергомоцистеинемия, атеросклероз и инсульт.…”

Section: болезни малых сосудов и сосудистая деменцияunclassified

“…Хроническая или острая гипоперфузия головного мозга приводит к оксидативному стрессу, который является основой или триггером патогенеза. У пациентов с СД выявлены морфофункциональные и ультраструктурные изменения ЭК, такие как снижение содержания митохондрий, усиление пиноцитоза, уменьшение количества плот-ных контактов, снижение плотности капилляров [113].…”

Section: болезни малых сосудов и сосудистая деменцияunclassified

Vascular endotelial dysfunction is a pathogenetic factor in the development of neurodegenerative diseases and cognitive impairment

Гончаров

Попова

Головкин

et al. 2020

V.M. BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY

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The amount of publications devoted to the endothelial cells, on the one hand, and neurological diseases, on the other hand, has been growing rapidly in recent years. Nevertheless, the relationship between the endothelial monolayer and the cells of the nervous system remains poorly studied. This review presents the available information about endothelial markers, molecular and cellular mechanisms for maintaining the integrity of the endothelial monolayer and the violations in some acute and chronic neuropsychiatric diseases. At the molecular level, the most important pathogenetic link in endothelial dysfunction is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species. Genetic and epigenetic factors that cause these disorders and their cause-and-effect relationships are considered. Of the genetic diseases, the most studied are monogenic diseases associated with impaired blood-brain barrier integrity: this is a deficiency of protein molecules that ensure glucose transport, structural and functional integrity of tight junctions and the basement membrane of endothelial cells themselves, as well as mutations in pericytes and smooth muscle cells. Mutations that increase the risk of developing known neurodegenerative diseases, but are also the cause of cerebrovascular pathology, are less studied. The small vessel diseases constitute a whole group of primarily epigenetically caused diseases, the clinical consequence of which is often vascular dementia. Special attention is paid to one of the least studied problems—the pathogenesis of toxicological diseases that occur at different times after acute and chronic organophosphate poisoning. Microangiopathies caused by damage to the endothelium in the central and peripheral nervous systems can be the main cause for the development of delayed effects in organophosphate poisoning. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of the nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.

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“…Astrogliosis has been shown to increase linearly with cognitive decline and is strongly associated with plaques and tangle formation (Serrano-Pozo et al 2011). On the other hand in VaD, astrogliosis and astroglial endfeet swelling has been implicated as one of the triggering factors for vascular damage (Price et al 2018;Wang et al 2018). In both instances, reactive astrogliosis is a commonality of the two diseases associated with the production of pro-inflammatory cytokines such as IL-6, which is strongly upregulated in the PP model at 6 and 9 months.…”

Section: Reproducibility In Postmortem Tissue From Ad and Vascular Dementioning

confidence: 99%

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Bathini

Dupanloup

Zenaro

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. To date, very few mouse models reproduce the pathophysiological progression of sporadic AD, while the majority of studies have employed transgenic animals reproducing the familial form.MethodsWe have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL).ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD shows a general tendency of the genes to decline except for GFAP.ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-AD, with progressive tau hyperphosphorylation, changes in microglia morphology, and gene reprogramming reflecting the increased neuroinflammation and the loss of neuronal functionality seen to some extent in humans.

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Dysfunction of Cerebrovascular Endothelial Cells: Prelude to Vascular Dementia

Cited by 123 publications

References 347 publications

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

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

Vascular endotelial dysfunction is a pathogenetic factor in the development of neurodegenerative diseases and cognitive impairment

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

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