Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure

Takane, Koki; Hasegawa, Yu; Lin, Bo; Koibuchi, Nobutaka; Cao, Cheng; Yokoo, Takashi; Kim‐Mitsuyama, Shokei

doi:10.1161/jaha.116.004897

Cited by 29 publications

(38 citation statements)

References 51 publications

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“…AngII infusion impaired both Wt-AngII and Tg-AngII rats in the MWM adaptation of a delayed match-sample test, a spatial task that tests working memory and behavioral flexibility, consistent with the clinical studies on the cognitive effects of hypertension (Raz et al, 2003;Vicario et al, 2005;Li et al, 2016). Previous studies have found histological and cognitive effects of AngII infusion or AngII blockade to be independent of blood pressure, which has been attributed to the central effects of AngII (Tedesco et al, 2002;Iadecola and Gorelick, 2004;Takeda et al, 2009;Capone et al, 2011;Hajjar et al, 2012;Takane et al, 2017), though these studies did not explicitly assess for white matter changes. It remains a possibility that high blood pressure alone, independently of AII, induces astrocytosis in the WM.…”

Section: Discussionsupporting

confidence: 83%

Hypertension and Pathogenic hAPP Independently Induce White Matter Astrocytosis and Cognitive Impairment in the Rat

Levit

Cheng

Hough

et al. 2020

Front. Aging Neurosci.

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Hypertension is recognized as a risk factor for Alzheimer disease, but the causal link remains undetermined. Although astrocytes and microglia play an important role in maintaining the neurovascular unit, astrocytes and microglia have been understudied in comorbid models of hypertension and Alzheimer disease. In this study, male transgenic Fischer 344 rats (TgAPP21) overexpressing a pathogenic human amyloid precursor protein received 8 weeks of Angiotensin II infusion to increase blood pressure, and the rats were evaluated for astrocytosis, microgliosis, and cognitive function. A linear relationship between astrocytosis and blood pressure was observed in the corpus callosum and cingulum of wildtype rats, with hypertensive wildtype rats matching the elevated baseline astrocytosis seen in normotensive transgenic rats. In contrast, hypertensive transgenic rats did not demonstrate a further increase of astrocytosis, suggesting a deficient response. Angiotensin II infusion did not affect activation of microglia, which were elevated in the white matter and hippocampus of transgenic rats. Angiotensin II infusion did impair both wildtype and transgenic rats' executive functions in the Morris Water Maze. These results present important implications for the interaction between hypertension and pathogenic human amyloid precursor protein expression, as Angiotensin II infusion produced cognitive impairments in both genotypes, but transgenic rats were additionally impaired in developing a normal astrocytic response to elevated blood pressure.

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Section: Discussionsupporting

confidence: 83%

Hypertension and Pathogenic hAPP Independently Induce White Matter Astrocytosis and Cognitive Impairment in the Rat

Levit

Cheng

Hough

et al. 2020

Front. Aging Neurosci.

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“…ANG II signaling through AT 1 R promotes neuroinflammation in a mouse model of Alzheimer's disease termed 5X familial AD (5XFAD). ICV infusion of ANG II impaired cognitive function in 5XFAD mice, which was associated with hippocampal inflammation, oxidative stress, and increased amyloid-␤ deposition (1029). Telmisartan prevents neuroinflammation by suppression of lipopolysaccharideinduced NO production from inducible NO synthase, and TNF-␣ and IL-1␤ secretion by BV2 microglia.…”

Section: Ang II Signaling In Cognitive Dysfunction Dementia and mentioning

confidence: 94%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

821

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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“…Studies performed in vitro have shown that Ang-II reduces BBB permeability and promotes tight junction expression in developing BBB endothelial cell monolayers (Wosik et al, 2007), but increases permeability when added to already established monolayers (Fleegal-DeMotta, Doghu, & Banks, 2009). BBB-disruptive effects of Ang-II were also found in vivo, though in the context of injury, disease (Takane et al, 2017), or pre-induced hypertension. In these models, Ang-II was introduced either directly into the CNS via infusion (Li et al, 2016) or indirectly via BBB disruption (Biancardi, Son, Ahmadi, Filosa, & Stern, 2014)that permitted entry of Ang-II (alongside other blood-borne factors) from circulation.…”

Section: Do Astrocyte-secreted Factors Maintain the Blood-brain Barrier?mentioning

confidence: 96%

Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

Heithoff

George

Phares

et al. 2020

Preprint

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224/250 words)In the adult brain, multiple cell types are known to produce factors that regulate blood-brain barrier properties, including astrocytes. Yet several recent studies disputed a role for mature astrocytes at the blood-brain barrier. To determine if astrocytes contribute a non-redundant and necessary function in maintaining the adult blood-brain barrier, we used a mouse model of tamoxifen-inducible astrocyte ablation. In adult mice, tamoxifen induction caused sparse apoptotic astrocyte cell death within 2 hours. Indicative of BBB damage, leakage of the small molecule Cadaverine and the large plasma protein fibrinogen into the brain parenchyma indicative of BBB damage was detected as early as astrocyte ablation was present. Vessels within and close to regions of astrocyte loss had lower expression of the tight junction protein zonula occludens-1 while endothelial glucose transporter 1 expression was undisturbed.Cadaverine leakage persisted for several weeks suggesting a lack of barrier repair. This is consistent with the finding that ablated astrocytes were not replaced. Adjacent astrocytes responded with partial non-proliferative astrogliosis, characterized by morphological changes and delayed phosphorylation of STAT3, which restricted dye leakage to the brain and vessel surface areas lacking coverage by astrocytes one month after ablation. In conclusion, astrocytes are necessary to maintain blood-brain barrier integrity in the adult brain. Blood-brain barrier-regulating factors secreted by other cell types, such as pericytes, are not sufficient to compensate for astrocyte loss. Main Points (250 characters)Mature astrocytes are necessary for maintenance of endothelial tight junctions in the adult brain.Ablated astrocytes are not replaced by proliferation or process extension of neighboring astrocytes resulting in long-term blood-brain barrier damage.

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Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure

Cited by 29 publications

References 51 publications

Hypertension and Pathogenic hAPP Independently Induce White Matter Astrocytosis and Cognitive Impairment in the Rat

Hypertension and Pathogenic hAPP Independently Induce White Matter Astrocytosis and Cognitive Impairment in the Rat

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

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