Effects of senescence and angiotensin II on expression and processing of amyloid precursor protein in human cerebral microvascular endothelial cells

Sun, Ruohan; He, Tongrong; Pan, Yujun; Katušić, Zvonimir S.

doi:10.18632/aging.101362

Cited by 18 publications

(14 citation statements)

References 75 publications

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“…Emergent evidence suggests that Ang II impacts amyloid precursor protein (APP) metabolism in cerebral microvascular endothelial cells through the Ang II type 2 receptor (AT2R) [65]. The AT2R-mediated action of Ang II on senescent primary human brain microvascular endothelial cells aggravated senescence-induced distortion of APP processing, adding therefore to the development of cerebral amyloid angiopathy and consequently to Alzheimer's disease pathology [65]. Further experiments are warranted to investigate AT2R involvement as a potential therapeutic target for Alzheimer's disease management.…”

Section: Other Novel Ras Components: At2 and At4 Receptorsmentioning

confidence: 99%

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

Noureddine

Altara

Fan

et al. 2020

IJMS

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The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

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Section: Other Novel Ras Components: At2 and At4 Receptorsmentioning

confidence: 99%

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

Noureddine

Altara

Fan

et al. 2020

IJMS

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“…Moreover, physiologic expression of APP in brain ECs is required to maintain normal eNOS expression, leading to the suggestion that disturbed metabolism of APP in mutant APP models of AD may lead to impaired expression of eNOS and vascular dysfunction [79]. Furthermore, senescence of human brain ECs was accompanied by increased levels of BACE-1 and Aβ 1−40 , and the latter was reversed by treatment with a BACE-1 inhibitor [80]. And absence of eNOS increased Aβ pathology in Tg-5xFAD mice [81].…”

Section: Discussionmentioning

confidence: 99%

Mouse models of Alzheimer’s disease cause rarefaction of pial collaterals and increased severity of ischemic stroke

2018

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Vascular dysfunction contributes to the progression and severity of Alzheimer’s disease (AD). Patients with AD also sustain larger infarctions after ischemic stroke; however, the responsible mechanisms are unknown. Pial collaterals are the primary source of protection in stroke. Unfortunately, natural aging and other vascular risk factors cause a decline in collateral number and diameter (rarefaction) and an increase in stroke severity. Herein, we tested the hypothesis that AD accelerates age-induced collateral rarefaction and examined potential underlying mechanisms. Triple and double transgenic mouse models of AD both sustained collateral rarefaction by 8 months of age, well before the onset of rarefaction caused by aging alone (16 months of age). Rarefaction, which did not progress further at 18 months of age, was accompanied by a twofold increase in infarct volume after MCA occlusion. AD did not induce rarefaction of similarly sized pial arterioles or penetrating arterioles. Rarefaction was minimal and occurred only at 18 months of age in a parenchymal vascular amyloid-beta model of AD. Rarefaction was not associated with amyloid-beta deposition on collaterals or pial arteries, nor was plaque burden or CD11b + cell density greater in brain underlying the collateral zones versus elsewhere. However, rarefaction was accompanied by increased markers of oxidative stress, inflammation, and aging of collateral endothelial and mural cells. Moreover, rarefaction was lessened by deletion of CX 3 CR1 and prevented by overexpression of eNOS. These findings demonstrate that mouse models of AD promote rarefaction of pial collaterals and implicate inflammation-induced accelerated aging of collateral wall cells. Strategies that reduce vascular inflammation and/or increase nitric oxide may preserve collateral function. Electronic supplementary material The online version of this article (10.1007/s10456-018-9655-0) contains supplementary material, which is available to authorized users.

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“…While the pathological outcome of APP dysregulation is mainly associated to its overexpression, recent studies showed that APP expression levels tend to decrease with age [ 59 , 60 ], and APP-knockout mice show age-dependent cognitive deficit and impaired locomotor activity [ 61 , 62 ]. Moreover, senescent brains showed an increase of amyloidogenic processing mediated by BACE1 [ 63 ], indicating that amyloid-β peptides accumulation is not necessarily associated with APP overexpression.…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β Precursor Protein APP Down-Regulation Alters Actin Cytoskeleton-Interacting Proteins in Endothelial Cells

Ristori

Cicaloni

Salvini

et al. 2020

Cells

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The amyloid-β precursor protein (APP) is a ubiquitous membrane protein often associated with Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Despite its role in the development of the pathogenesis, APP exerts several physiological roles that have been mainly investigated in neuronal tissue. To date, the role of APP in vasculature and endothelial cells has not been fully elucidated. In this study, we used molecular and proteomic approaches to identify and investigate major cellular targets of APP down-regulation in endothelial cells. We found that APP is necessary for endothelial cells proliferation, migration and adhesion. The loss of APP alters focal adhesion stability and cell–cell junctions’ expression. Moreover, APP is necessary to mediate endothelial response to the VEGF-A growth factor. Finally, we document that APP propagates exogenous stimuli and mediates cellular response in endothelial cells by modulating the Scr/FAK signaling pathway. Thus, the intact expression and processing of APP is required for normal endothelial function. The identification of molecular mechanisms responsible for vasoprotective properties of endothelial APP may have an impact on clinical efforts to preserve and protect healthy vasculature in patients at risk of the development of cerebrovascular disease and dementia including AD and CAA.

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Effects of senescence and angiotensin II on expression and processing of amyloid precursor protein in human cerebral microvascular endothelial cells

Cited by 18 publications

References 75 publications

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

Mouse models of Alzheimer’s disease cause rarefaction of pial collaterals and increased severity of ischemic stroke

Amyloid-β Precursor Protein APP Down-Regulation Alters Actin Cytoskeleton-Interacting Proteins in Endothelial Cells

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