ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy

Carrano, Anna; Snkhchyan, Hripsime; Kooij, Gijs; Pol, Susanne van der; Horssen, Jack van; Veerhuis, Robert; Hoozemans, Jeroen J. M.; Rozemüller, Annemieke; Vries, Helga E. de

doi:10.1016/j.neurobiolaging.2013.09.015

Cited by 47 publications

(52 citation statements)

References 56 publications

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“…It is not known whether the early decrease in P-gp expression in adult aging is also associated with TGF-B1 levels. It has also been demonstrated in capillaries affected by amyloid angiopathy that decreased expression of P-gp receptor protein is associated with decreased P-gp mRNA expression (Carrano et al 2014). In our study, the biphasic nature of age-related P-gp protein expression seen in both rats and humans is related to a similar biphasic expression of P-gp mRNA in the rat model (Chiu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Osgood

Miller

Messier

et al. 2017

Neurobiology of Aging

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Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta peptides (Aβ) and other macromolecules in the brains of the elderly and in Alzheimer’s disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier (BBB) are significantly altered with age: the efflux transporters LRP-1 and P-gp are reduced, whereas the influx transporter RAGE is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene mRNA at 3, 6, 9, 12, 15, 20, 30 and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by qPCR. LRP-1 and P-gp mRNA were significantly reduced in aging, and RAGE was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in BBB receptor expression and Aβ accumulation.

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Section: Discussionmentioning

confidence: 99%

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Osgood

Miller

Messier

et al. 2017

Neurobiology of Aging

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“…CAA is associated with cognitive decline, and represents a hallmark of AD and an important cause of vascular dementia. It was found in different mice models and human tissue, that ABCB1 expression is decreased in patients with capillary CAA (capCAA), a disease characterized by Aβ-deposits in the cerebral capillaries (Carrano et al, 2014). The decline of the levels of the transporter at the BBB occurs during normal aging, and is positively correlated with the accumulation of Aβ (Silverberg et al, 2010).…”

Section: Abc Transportersmentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

132

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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“…A direct transport of Aβ proteins by P‐gp could be proven, and knockout as well as inhibition of P‐gp led to an Aβ overload of the corresponding cells . AD‐affected vessels were shown to have compressed expression levels of P‐gp, which could be attributed to a downregulation of P‐gp by the very same Aβ proteins . Reconstitution of P‐gp and, therefore, restoration of its formerly impaired transport function showed to delay the disease progress …”

Section: Introductionmentioning

confidence: 99%

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

Wiese

Stefan

2019

Medicinal Research Reviews

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Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by cross‐resistance of cells against chemotherapeutic agents, which are used for treatment of e.g., cancer, bacterial infections, or human immunodeficiency virus (HIV) infections. One group of proteins that combines all three stated aspects—the metabolism and distribution of drugs as well as their own regulation—is adenosine triphosphate‐binding cassette (ABC) transporters. These efflux pumps use the energy of adenosine triphosphate hydrolysis for drug translocation from the membrane and the cytosol to the extracellular space, often with cotransport of a cosubstrate. Multidrug resistance‐associated protein 1 (MRP1, ABCC1) had been discovered as one major key player in cancer‐related MDR. The xenobiotic substrates include anthracyclines, vinca alkaloids, podophyllotoxins, as well as glutathione (GSH)‐adducts of certain cytostatics. Contrary to other transport proteins involved in cancer‐related MDR the activity of MRP1 is related to the GSH content of cells. A modern strategy to overcome MRP1‐associated MDR is besides its inhibition the activation of GSH efflux, enforcing cell death due to cellular stress. In addition, it has recently been found that MRP1 contributes to the β‐amyloid protein clearance in Alzheimer's disease (AD). Collectively, transport activation of MRP1 is of therapeutic value, and furthermore helps to elucidate the transport protein function and the mechanisms behind it. This review is meant to summarize the known concepts of MRP1 activation, which might contribute to a further understanding of MRP1 in particular and ABC transporters in general.

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ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy

Cited by 47 publications

References 56 publications

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

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