Brain Pericytes ABCA1 Expression Mediates Cholesterol Efflux but not Cellular Amyloid-β Peptide Accumulation

Saint-Pol, Julien; Vandenhaute, Elodie; Boucau, Marie-Christine; Candela, Pietra; Dehouck, Lucie; Cecchelli, Roméo; Dehouck, Marie‐Pierre; Fénart, Laurence; Gosselet, Fabien

doi:10.3233/jad-2012-112090

Cited by 60 publications

(80 citation statements)

References 61 publications

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“…In the brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH-chol), which is an endogenous ligand for LXR. 97 Shimizu et al demonstrated that the GDNF, secreted from the brain and peripheral nerve pericytes, is one of the key molecules responsible for the up-regulation of claudin-5 expression and the permeability in the BBB. 98 Furthermore, pericytes are able to internalize the amyloid-b peptides, which accumulate in brain of Alzheimer's disease patients.…”

Section: Astrocytesmentioning

confidence: 99%

Age-associated physiological and pathological changes at the blood–brain barrier: A review

Erdő

Dénès

Lange

2016

J Cereb Blood Flow Metab

352

260

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The age-associated decline of the neurological and cognitive functions becomes more and more serious challenge for the developed countries with the increasing number of aged populations. The morphological and biochemical changes in the aging brain are the subjects of many extended research projects worldwide for a long time. However, the crucial role of the blood-brain barrier (BBB) impairment and disruption in the pathological processes in age-associated neurodegenerative disorders received special attention just for a few years. This article gives an overview on the major elements of the blood-brain barrier and its supporting mechanisms and also on their alterations during development, physiological aging process and age-associated neurodegenerative disorders (Alzheimer's disease, multiple sclerosis, Parkinson's disease, pharmacoresistant epilepsy). Besides the morphological alterations of the cellular elements (endothelial cells, astrocytes, pericytes, microglia, neuronal elements) of the BBB and neurovascular unit, the changes of the barrier at molecular level (tight junction proteins, adheres junction proteins, membrane transporters, basal lamina, extracellular matrix) are also summarized. The recognition of new players and initiators of the process of neurodegeneration at the level of the BBB may offer new avenues for novel therapeutic approaches for the treatment of numerous chronic neurodegenerative disorders currently without effective medication. KeywordsAging, blood-brain barrier, endothelial cells, neurodegenerative disorders, transport systems Structure of the blood-brain barrier (BBB)Homeostasis of the extracellular microenvironment in the neural tissue of the brain as well as its protection against neurotoxic compounds and variations in the composition of the blood are important for normal function of the neurons. It is warranted by a structure formed between blood and brain, which is therefore called the BBB.1 Clear evidence for the existence of this permeability barrier in the brain emerged in 1909 with the demonstration by Edwin Goldman (a South African-German) that a dye injected into the blood stream of a rat stained the whole body -except for the brain and spinal cord. The opposite was also true: injection of the dye into the cerebral ventricles stained the brain and spinal cord but not the rest of the body. 2,3 This occurs because most organs of the body are perfused by capillaries lined with endothelial cells (ECs) that have small pores (fenestrations) to allow for the rapid movement of small molecules into the organ interstitial fluid from the circulation. However, the capillary endothelium of the brain and spinal cord lack these pores because the ECs of brain capillary are connected to each other by continuous tight junctions (TJs), produced by the interaction of several transmembrane proteins that project into and seal the paracellular pathway.3-5 The interaction of these junctional proteins effectively blocks the free diffusion of

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Section: Astrocytesmentioning

confidence: 99%

Age-associated physiological and pathological changes at the blood–brain barrier: A review

Erdő

Dénès

Lange

2016

J Cereb Blood Flow Metab

352

260

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“…This finding was supported by in vitro studies demonstrating ABCA1 significant role in the regulation of neuronal cholesterol efflux to apoE and in suppression of APP processing to generate Aβ peptides, 92,94 contradicting those reported by Fukumoto et al 106 Furthermore, results from in vitro studies performed in pericytes demonstrated that treatment of primary pericytes culture with 24S-OH-cholesterol, a cholesterol metabolite and a natural agonist of LXR, increased expression of ABCA1, and such an increase in ABCA1 expression correlated with cholesterol transfer to apoE, apoA-I, and HDL particles, the key players in brain cholesterol homeostasis and amyloid accumulation and deposition, and its inhibition decreased this efflux. 73 Yet the increase in ABCA1 expression was not associated with any change in Aβ 40 and Aβ 42 peptide accumulation inside pericytes. 73 Besides, in vitro inhibition studies supported the role of ABCA1 in Aβ production.…”

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confidence: 99%

“…73 Yet the increase in ABCA1 expression was not associated with any change in Aβ 40 and Aβ 42 peptide accumulation inside pericytes. 73 Besides, in vitro inhibition studies supported the role of ABCA1 in Aβ production. Recently, in their in vitro study, Kim et al demonstrated using the mouse neuroblastoma N2a cells that suppression of ABCA1 expression by miR-106b impaired cellular cholesterol efflux and increased the levels of secreted Aβ.…”

mentioning

confidence: 99%

“…Unlike ABCB1, ABCA1 does not directly transport Aβ. 72,73 In Abca1 knockout mice, the elimination of cerebral microinjected 125 I-Aβ 40 across the BBB was not significantly different from that of wild type mice, suggesting that most likely in AD ABCA1 affects the production and/or degradation system of Aβ rather than its efflux transport across the BBB. 72 ABCA1 regulates both the level of apoE as well as its state of lipidation via regulation of neuronal cholesterol efflux to apoE.…”

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confidence: 99%

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Role of ABC Transporters in the Pathogenesis of Alzheimer’s Disease

Abuznait

Kaddoumi

2012

ACS Chem. Neurosci.

111

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of age-related dementia that begins with memory loss and progresses to include severe cognitive impairment. A major pathological hallmark of AD is the accumulation of beta amyloid peptide (Aβ) in senile plaques in the brain of AD patients. The exact mechanism by which AD takes place remains unknown. However, an increasing number of studies suggests that ATP-binding cassette (ABC) transporters, which are localized on the surface of brain endothelial cells of the bloodbrain barrier (BBB) and brain parenchyma, may contribute to the pathogenesis of AD. Recent studies have unraveled important roles of ABC transporters including ABCB1 (P-glycoprotein, P-gp), ABCG2 (breast cancer resistant protein, BCRP), ABCC1 (multidrug resistance protein 1, MRP1), and the cholesterol transporter ABCA1 in the pathogenesis of AD and Aβ peptides deposition inside the brain. Therefore, understanding the mechanisms by which these transporters contribute to Aβ deposition in the brain is important for the development of new therapeutic strategies against AD. This review summarizes and highlights the accumulating evidence in the literature which describe the role of altered function of various ABC transporters in the pathogenesis and progression of AD and the implications of modulating their functions for the treatment of AD. KEYWORDS: ABC transporters, Alzheimer's disease, blood-brain barrier, ABCA1, P-glycoprotein, MRP1, BCRP A lzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of age-related dementia that begins with memory loss and progresses to include severe cognitive impairment.1 The pathogenesis of AD is complex, and involves molecular, genetic, cellular, and physiological alterations to the brain and blood-brain barrier (BBB) that are still not completely understood.2,3 The prevalence of AD is going up rapidly worldwide, with about 30 million people suffering from this disease nowadays, and it has an increasing socioeconomic impact. 4 Despite the huge demand for treatments, existing drugs have limited or no efficacy for AD. 5,6 AD is characterized by a significant loss of neurons and atrophy of the hippocampus and cerebral cortex.7 It begins as mild short-term memory disturbances and ends in total loss of cognition and executive functions.8−10 The neuropathology of AD is characterized by two pathogenic hallmarks: the intraneuronal neurofibrillary tangle (NFT) and the extracellular amyloid plaque. 11,12 NFTs are largely composed of hyperphosphorylated fibrillar forms of a protein called microtubule associated protein tau which accumulates in the entorhinal cortex and the pyramidal neurons of the CA1 region of the hippocampus and subiculum.7 The well-known amyloid cascade hypothesis suggests that AD is precipitated by the accumulation of amyloid plaques that are mainly composed of fibrils of peptides collectively known as beta amyloid (Aβ) which are produced by the sequential cleavage of am...

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“…Ce type cellulaire, connu depuis plus de 150 ans, semble essentiel à la physiologie ainsi qu'au maintien de l'intégrité de la BHE [9]. Cependant, peu de données sont disponibles concernant ces cellules et leur rôle précis, notamment dans la régulation de l'homéostasie cérébrale du cholestérol (probablement perturbée dans le cerveau des patients atteints de MA), reste encore peu exploré [10]. L'équipe de B. Zlokovic a ainsi démontré que la régulation de brale, les relations entre les produits de ce gène et la BHE restent cependant très peu étudiées.…”

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Apolipoprotéine E et intégrité de la barrière hémato-encéphalique

Gosselet

2012

Med Sci (Paris)

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Brain Pericytes ABCA1 Expression Mediates Cholesterol Efflux but not Cellular Amyloid-β Peptide Accumulation

Cited by 60 publications

References 61 publications

Age-associated physiological and pathological changes at the blood–brain barrier: A review

Age-associated physiological and pathological changes at the blood–brain barrier: A review

Role of ABC Transporters in the Pathogenesis of Alzheimer’s Disease

Apolipoprotéine E et intégrité de la barrière hémato-encéphalique

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