ABCG2- and ABCG4-Mediated Efflux of Amyloid-β Peptide 1-40 at the Mouse Blood-Brain Barrier

Minh, Tuan Nguyen; Noël-Hudson, Marie-Sophie; Ribes, Sandy; Besengez, Capucine; Smirnova, Maria; Cisternino, Salvatore; Buyse, Marion; Calon, Frédéric; Chimini, Giovanna; Chacun, Hélène; Scherrmann, Jean‐Michel; Farinotti, Robert; Bourasset, Fanchon

doi:10.3233/jad-2012-112189

Cited by 97 publications

(91 citation statements)

References 43 publications

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“…67 The pathways governing influx will be described in the next section. The cellular prion protein 68 and the multidrug transporters ABCG2 and 4 have also been shown to contribute to Ab efflux across the BBB, 69 although AD-relevant changes of these are presently unclear.…”

Section: Defects In Blood-brain Barrier Transporters That May Contribmentioning

confidence: 99%

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Erickson

Banks

2013

J Cereb Blood Flow Metab

447

363

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The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-b (Ab) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Ab pathology. Keywords: Alzheimer's disease; blood-brain barrier; cerebrospinal fluid; diabetes; inflammation; neurovascular unit INTRODUCTION Alzheimer's disease (AD) is the most common type of dementia, and affects B36 million individuals worldwide (http://www.alz. co.uk/research/world-report). The majority of individuals afflicted with AD initially present with symptoms of memory loss and cognitive impairment late in life (Z65 years old). These symptoms increase in severity as AD progresses, often become so debilitating that institutionalization is necessary, and are eventually fatal. Therefore, AD is a disease with tremendous socioeconomic cost. Because of the growing aged population and lack of treatments that can prevent or slow disease progression, future AD prevalence is expected to increase to an extent that it may threaten the sustainability of healthcare systems worldwide. This necessitates a global effort to better understand AD, with the goal of developing treatments that can prevent or slow AD progression. Journal of Cerebral BloodMuch of the focus in AD research has been on amyloid-b peptide (Ab) and tau, which are the protein constituents of the hallmark senile plaques and neurofibrillary tangles that pathologically define AD. The amyloid cascade hypothesis, initially proposed by Hardy and Higgins in 1992, 1 updated by Hardy and Selkoe in 2002, 2 and still a prevalent focus of AD research today, states that deposition of Ab in the brain is the initiating event in AD. Although the hypothesis remains generally accepted, it is also increasingly evident that Ab plays a complex, multifaceted role in AD progression. In rare, familial forms of AD, mutations in the Ab precursor protein (APP) or in presenilin proteins, the enzymes that cleave Ab from APP, cause increased Ab deposition. In the remainder of AD cases, it is thought that Ab deposition results from deficient clearance. 2 Multiple routes of clearance have been elucidat...

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Section: Defects In Blood-brain Barrier Transporters That May Contribmentioning

confidence: 99%

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Erickson

Banks

2013

J Cereb Blood Flow Metab

447

363

View full text Add to dashboard Cite

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“…Shen et al (2010) used cell culture experiments to show that ABCG2 prevents cells from reactive oxygen stress via modulation of the NF-κβ pathway. Other studies found a contribution of ABCG2 to Aβ transport in vitro using different cell lines (Candela et al, 2010; Do et al, 2012; Tai et al, 2009). Do et al (2012) also proposed ABCG4 to be an Aβ40 transporter.…”

Section: Abc-transporters and Aβ – 13 Years Of Researchmentioning

confidence: 92%

Alzheimer’s and ABC transporters — new opportunities for diagnostics and treatment

Pahnke

Langer

Krohn

2014

Neurobiology of Disease

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Much has been said about the increasing number of demented patients and the main risk factor ‘age’. Frustratingly, we do not know the precise pattern and all modulating factors that provoke the pathologic changes in the brains of affected elderly. We have to diagnose early to be able to stop the progression of diseases that irreversibly destroy brain substance. Familiar AD cases have mislead some researchers for almost 20 years, which has unfortunately narrowed the scientific understanding and has, thus, lead to insufficient funding of independent approaches. Therefore, basic researchers hardly have been able to develop causative treatments and clinicians still do not have access to prognostic and early diagnostic tools. During the recent years it became clear that insufficient Aβ export, physiologically facilitated by the ABC transporter superfamily at the brain’s barriers, plays a fundamental role in disease initiation and progression. Furthermore, export mechanisms that are deficient in affected elderly are new targets for activation and, thus, treatment, but ideally also for prevention. In sporadic AD disturbed clearance of β-amyloid from the brain is so far the most important factor for its accumulation in the parenchyma and vessel walls. Here, we review findings about the contribution of ABC transporters and of the perivascular drainage/glymphatic system on β-amyloid clearance. We highlight their potential value for innovative early diagnostics using PET and describe recently described, effective ABC transporter-targeting agents as potential causative treatment for neurodegenerative proteopathies/dementias.

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“…ABCB1 deficiency increases Aβ42 levels in the hippocampus of P-gp-null transgenic mouse models of AD (AD mice) (Cirrito et al 2005). Aβ peptides are transferred by ABCG2, which is one of the major efflux pumps in the brain along with ABCB1 (Do et al 2012). On the other hand, ABCC1 knockout mice showed a significant increase in cerebral Aβ accumulation compared with either ABCB1 or ABCG2 knockout mice (Krohn et al 2011), and it was indicated that ABCB1 and ABCG2 suppress the entry of plasma Aβ into the brain (Tai et al 2009;Xiong et al 2009).…”

Section: Introductionmentioning

confidence: 98%

“…LRP2 contributes to the transport of Aβ in complex with apolipoprotein J (Zlokovic et al 1996Hammad et al 1997). ATP-binding cassette (ABC) transporters such as ABCB1 (MDR1, multidrug resistance protein 1; P-gp, P-glycoprotein), ABCC1 (MRP1 multidrug resistance-associated protein 1), ABCG2 (BCRP, breast cancer resistance protein) and ABCG4 are also supposed to be involved in the clearance of Aβ peptides from the brain (Lam et al 2001;Do et al 2012;Krohn et al 2011;reviewed by Abuznait and Kaddoumi 2012;Gosselet et al 2013). ABCB1 deficiency increases Aβ42 levels in the hippocampus of P-gp-null transgenic mouse models of AD (AD mice) (Cirrito et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, ABCC1 knockout mice showed a significant increase in cerebral Aβ accumulation compared with either ABCB1 or ABCG2 knockout mice (Krohn et al 2011), and it was indicated that ABCB1 and ABCG2 suppress the entry of plasma Aβ into the brain (Tai et al 2009;Xiong et al 2009). ABCG4 was assumed to mediate the transport of Aβ at the mouse BBB (Do et al 2012). Conversely, the receptor for advanced glycation end products (RAGE) transports Aβ from the blood to the brain (Deane et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood–cerebrospinal fluid barrier in human brain

Matsumoto

Chiba

Fujihara

et al. 2015

Histochem Cell Biol

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A large number of previous reports have focused on the transport of amyloid-β peptides through cerebral endothelial cells via the blood-brain barrier, while fewer reports have mentioned the transport through the choroid plexus epithelium via the blood-cerebrospinal fluid barrier. Concrete roles of these two pathways remain to be clarified. In this study, we immunohistochemically examined the expression of transporters/receptors that are supposed to be related to the clearance of amyloid-β peptides in the choroid plexus epithelium, the ventricular ependymal cells and the brain microvessels, using seven autopsied human brains. In the choroid plexus epithelium, immunoreactivity for low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), LRP2, formylpeptide receptor-like 1 (FPRL1), ATP-binding cassette (ABC) transporter-A1 (ABCA1), ABCC1 and ABCG4 was seen in 7 of 7 brains, while that for ABCB1, ABCG2, RAGE and CD36 was seen in 0-2 brains. In the ventricular ependymal cells, immunoreactivity for CD36, LDLR, LRP1, LRP2, FPRL1, ABCA1, ABCC1 and ABCG4 was seen in 6-7 brains, while that for ABCB1, ABCG2 and RAGE was seen in 0-1 brain. Immunoreactivity for insulin-degrading enzyme (IDE) was seen in three and four brains in the choroid plexus epithelium and the ventricular ependymal cells, respectively. In addition, immunoreactivity for LDLR, ABCB1 and ABCG2 was seen in over 40 % of the microvessels (all seven brains), and that for FPRL1, ABCA1, ABCC1 and RAGE was seen in over 5 % of the microvessels (4-6 brains), while that for CD36, IDE, LRP1, LRP2 and ABCG4 was seen in less than 5 % of the microvessels (0-2 brains). These findings may suggest that these multiple transporters/receptors and IDE expressed on the choroid plexus epithelium, ventricular ependymal cells and brain microvessels complementarily or cooperatively contribute to the clearance of amyloid-β peptides from the brain.

show abstract

ABCG2- and ABCG4-Mediated Efflux of Amyloid-β Peptide 1-40 at the Mouse Blood-Brain Barrier

Cited by 97 publications

References 43 publications

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Alzheimer’s and ABC transporters — new opportunities for diagnostics and treatment

Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood–cerebrospinal fluid barrier in human brain

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