ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ<sub>1–40</sub>Peptides

Xiong, Huaqi; Callaghan, Debbie; Jones, Aimee; Bai, Jianying; Rasquinha, Ingrid; Smith, Catherine Delano; Pei, Ke; Walker, Douglas G.; Lue, Lih‐Fen; Stanimirovic, Danica; Zhang, Wandong

doi:10.1523/jneurosci.5103-08.2009

Cited by 186 publications

(200 citation statements)

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“…6 However, in our previous study, LRP1 did not show a significant difference at 2 months between noninjured and jTBI animals. 4 Interestingly, several other proteins have been proposed to participate in Ab clearance like other transporters (ABCA1 and ABCA2) 28,29 or like the receptor a5b1 integrin. 30 In addition, various basement membrane proteins, Figure 4.…”

Section: Discussionmentioning

confidence: 99%

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Jullienne

Roberts

Pop

et al. 2014

J Cereb Blood Flow Metab

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In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Ab) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Ab clearance. Rodent-Ab staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood-brain barrier alongside vascular dysfunction and altered Ab trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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Section: Discussionmentioning

confidence: 99%

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Jullienne

Roberts

Pop

et al. 2014

J Cereb Blood Flow Metab

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“…124 Optical imaging analyses of live animals and their brains showed that Abcg2-null mice significantly accumulated more Aβ in their brains than wildtype mice, suggesting ABCG2 may act as a gatekeeper at the BBB to prevent blood Aβ from entering into brain. 124 This role was further confirmed by in vitro studies utilizing ABCG2 overexpressing cells. The results demonstrated ABCG2 to restrict the apical-to-basolateral permeability of Aβ isoforms, suggesting a role for this efflux transporter in preventing bloodborne Aβ peptides from entering the brain, but not in transporting the brain Aβ into blood.…”

Section: ■ Abcg Family Abcg2 (Breast Cancer Resistance Protein Bcrp)mentioning

confidence: 99%

“…122,123 ABCG2 shows substrate overlap with ABCB1 and its involvement in Aβ peptides transport was suggested at the microvessel cells level acting as gatekeeper at the BBB to prevent blood Aβ peptides from entering into the brain. 62,124,125 The role of ABCG2 in Aβ extrusion at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of labeled Aβ. 124 Optical imaging analyses of live animals and their brains showed that Abcg2-null mice significantly accumulated more Aβ in their brains than wildtype mice, suggesting ABCG2 may act as a gatekeeper at the BBB to prevent blood Aβ from entering into brain.…”

Section: ■ Abcg Family Abcg2 (Breast Cancer Resistance Protein Bcrp)mentioning

confidence: 99%

“…62,124,125 The role of ABCG2 in Aβ extrusion at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of labeled Aβ. 124 Optical imaging analyses of live animals and their brains showed that Abcg2-null mice significantly accumulated more Aβ in their brains than wildtype mice, suggesting ABCG2 may act as a gatekeeper at the BBB to prevent blood Aβ from entering into brain. 124 This role was further confirmed by in vitro studies utilizing ABCG2 overexpressing cells.…”

Section: ■ Abcg Family Abcg2 (Breast Cancer Resistance Protein Bcrp)mentioning

confidence: 99%

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

Abuznait

Kaddoumi

2012

ACS Chem. Neurosci.

110

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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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“…ATP-binding cassette transporters, as well as being involved in lipid metabolism, cholesterol efflux, and drug transport, are important in removing intracellular Aβ and are dysfunctional in AD; as they are ATP dependent, it has been suggested that reduced energy production could lead to a build-up of Aβ [239]. Specifically, both ABCG2 and ABCC1 have been found to be involved in Aβ transport [240,241]. Whether or not CBD may beneficially act through these transporters is difficult to gauge, as not only might they inhibit ABC-mediated transport of Aβ, but the reported IC 50 may also be too high to be relevant physiologically.…”

Section: Cbd Transporter Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ_1–40Peptides

Cited by 186 publications

References 57 publications

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

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

Molecular Targets of Cannabidiol in Neurological Disorders

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ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ1–40Peptides

Cited by 186 publications

References 57 publications

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

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

Molecular Targets of Cannabidiol in Neurological Disorders

Contact Info

Product

Resources

About

ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ_1–40Peptides