Simvastatin Protects against Amyloid β and HIV-1 Tat-Induced Promoter Activities of Inflammatory Genes in Brain Endothelial Cells

András, Ibolya E.; Rha, Geun Bae; Huang, Wen Cheng; Eum, Sung Yong; Romero, Ignacio A.; Hennig, Bernhard; Toborek, Michał

doi:10.1124/mol.107.042028

Cited by 40 publications

(39 citation statements)

References 41 publications

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“…These observations are consistent with the evidence that brain vascular dysfunction and the blood brain barrier (BBB) are playing important roles in amyloid pathology observed in AD [14]. Importantly, amyloid and HIV-1 potentiate their cerebrovascular toxicity by disrupting the integrity of the brain endothelium and stimulation of inflammatory responses [15, 16]. …”

Section: Introductionsupporting

confidence: 85%

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HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

András

Toborek

2014

Experimental Cell Research

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Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood-brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level.

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Section: Introductionsupporting

confidence: 85%

“…Cells were treated with Aβ (1–40) or Aβ (1–40) HiLyte at the concentration of 1 µM for 10 min or 1 h in complete medium. Similar treatment was shown to result in an uptake by the BBB [22] and stimulation of pro-inflammatory responses [15]. …”

Section: Methodsmentioning

confidence: 94%

HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

András

Toborek

2014

Experimental Cell Research

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“…63 Furthermore, a statin blocked amyloid β-induced proinflammatory reactions in HBMEC. 64 These results indicate that statins can be expected to attenuate diabetes-induced cognitive function via an inhibition of BBB permeability. Therefore, RAS blockade and treatment with statins may prevent BBB permeability, mainly though effects on the endothelium; however, it is not well known whether these approaches are actually effective for diabetic patients, so further clinical investigation is anticipated.…”

Section: Treatment Options In Diabetes-induced Bbb Disruptionmentioning

confidence: 87%

Neurovascular Coupling in Cognitive Impairment Associated With Diabetes Mellitus

Mogi

Horiuchi

2011

Circ J

109

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Although it is feared that diabetes-induced cognitive decline will become a major clinical problem worldwide in the future, the detailed pathological mechanism is not well known. Because patients with diabetes have various complications of vascular disease, with not only macrovascular but also microvascular disorders, vascular disorders in the brain are considered to be one of the mechanisms in diabetes-induced cognitive impairment. Indeed, disruption of the blood - brain barrier (BBB) has been observed in some diabetic patients and experimental diabetes models. Moreover, white matter lesions, part of the evidence of BBB dysfunction, are reported to be observed more frequently in patients with diabetes. Animal studies demonstrate that diabetes enhances BBB permeability through a decrease in the level of tight junction proteins and an increase in matrix metalloproteinase activity. However, there are several reports indicating that BBB disruption does not occur with diabetes. Therefore, the association of BBB breakdown with diabetes-induced cognitive impairment is not conclusive. Recently, neuronal diseases involving dementia have been induced experimentally through dysfunction of neurovascular coupling, which involves blood vessels, astrocytes and neutrons. Diabetes-induced cognitive decline may be induced via disruption of neurovascular coupling, with not only vascular disorder but also impairment of astrocytic trafficking. Here, the relation between vascular disorder and cognitive impairment in diabetes is discussed. (Circ J 2011; 75: 1042 - 1048

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“…Partial protection against Aβ 25−35 peptide-induced cell damage by carnosine, an endogenous antiglycating dipeptide with free radical scavenging activity, homocarnosine and β-alanine was described on a rat brain endothelial cell line [16]. Simvastatin effectively blocked the proinflammatory reactions induced by Aβ 1−40 peptide in a human brain endothelial cell line [69]. Tauroursodeoxycholic acid, an antiapoptotic endogenous bile acid inhibited the apoptosis of human brain cerebral endothelial cells triggered by the vasculotropic Aβ 1−40 E22Q mutant peptide [70].…”

Section: Protection Of Bbb As a New Therapeutical Approach In Admentioning

confidence: 99%

Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity

Deli

Veszelka

Csiszár

et al. 2010

JAD

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Abstract. Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1−42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1−42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease.

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Simvastatin Protects against Amyloid β and HIV-1 Tat-Induced Promoter Activities of Inflammatory Genes in Brain Endothelial Cells

Cited by 40 publications

References 41 publications

HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

Neurovascular Coupling in Cognitive Impairment Associated With Diabetes Mellitus

Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity

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