Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-β Production by Altering Nicastrin Maturation and Intracellular Localization

Michaki, Vasiliki; Guix, Francesc X.; Vennekens, Kristel M.; Munck, Sebastian; Dingwall, Colin; Davis, John B.; Townsend, Danyelle M.; Tew, Kenneth D.; Feiguin, Fabián; Strooper, Bart De; Dotti, Carlos G.; Wahle, Tina

doi:10.1074/jbc.m111.288258

Cited by 39 publications

(36 citation statements)

References 78 publications

(91 reference statements)

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“…120 These results were confirmed in vivo, where Abca2 knockout mice displayed reduced Nicastrin protein levels and decreased Aβ production without affecting APP levels. 120 Overall, the findings from this study suggested Abca2 as an important regulator of γ-secretase-mediated APP proteolysis and therefore of Aβ production.…”

supporting

confidence: 72%

“…121 On the other hand, in mammalian cells, siRNAmediated knockdown of Abca2 expression resulted in decreased Aβ production as a result of lowered γ-secretase processing of APP. 120 The authors showed that Abca2 knockdown affected the glycosylation pattern and subcellular localization of Nicastrin, one of the four γ-components including Presenilins 1 and 2, and Aph1, leading to altered γ-secretase complex formation. 120 These results were confirmed in vivo, where Abca2 knockout mice displayed reduced Nicastrin protein levels and decreased Aβ production without affecting APP levels.…”

mentioning

confidence: 99%

“…120 The authors showed that Abca2 knockdown affected the glycosylation pattern and subcellular localization of Nicastrin, one of the four γ-components including Presenilins 1 and 2, and Aph1, leading to altered γ-secretase complex formation. 120 These results were confirmed in vivo, where Abca2 knockout mice displayed reduced Nicastrin protein levels and decreased Aβ production without affecting APP levels. 120 Overall, the findings from this study suggested Abca2 as an important regulator of γ-secretase-mediated APP proteolysis and therefore of Aβ production.…”

mentioning

confidence: 99%

“…119,120 The overexpression of ABCA2 in N2a neuronal cells elevated endogenous APP expression and promoted amyloidogenic processing through β-secretase cleavage at the β′-site/ Glu11 of Aβ in APP to generate the β′-CTF/89 fragment. Cleavage of the β′-CTF/89 fragment by γ-secretase generates N-terminally truncated Aβ peptides that are linked with AD pathology.…”

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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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confidence: 72%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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“…This would be consistent with the observed increase in APP endocytosis in the primary mouse microglia cells lacking ABCA7. Comparable changes in APP processing for a related family member, ABCA2, that result from alterations in the trafficking of ␥-secretase components, particularly nicastrin, have been observed (61).…”

Section: Discussionmentioning

confidence: 99%

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

Satoh

Abe-Dohmae

Yokoyama

et al. 2015

Journal of Biological Chemistry

106

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Background:The ATP-binding cassette transporter A7 (ABCA7) is a risk factor for sporadic Alzheimer disease (AD). Results: Loss of ABCA7 promoted A␤ processing and pathology in cell culture and AD mouse models. Conclusion: Altered ABCA7 function may contribute to AD by impacting A␤ production in addition to clearance. Significance: AD-related risk factors may contribute to disease progression through multiple pathways.The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-␤ (A␤). Suppression of endogenous ABCA7 in several different cell lines resulted in increased ␤-secretase cleavage and elevated A␤. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid A␤42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble A␤ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble A␤ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas A␤ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased A␤ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility.Genome-wide association studies have identified the ATPbinding cassette transporter A7 (ABCA7) 2 as a susceptibility locus for late onset Alzheimer disease (LOAD) (1, 2). The single nucleotide polymorphisms (SNPs) associated with LOAD are distributed in various domains of the ABCA7 gene and include intronic SNPs and a coding sequence causing G1527A substitution. Studies have identified loci in different clusters, suggesting multiple sites within the ABCA7 gene associated with increased risk for AD (3). However, there is no indication that individuals with at-risk alleles display any differences in ABCA7 expression.ABCA7 is a member of the ATP-binding cassette transporter family largely involved in lipid transport and homeostasis (4). Its highly homologous member ABCA1 has also been linked to LOAD through cholesterol and processing of the amyloid precursor protein (5-7). Overexpression of ABCA7 resulted in a significant decrease in amyloid-...

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A Multisystemic Approach Revealed Aminated Polystyrene Nanoparticles‐Induced Neurotoxicity

Schröter,

Jentsch,

Maglioni

et al. 2023

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Exposure to plastic nanoparticles has dramatically increased in the last 50 years, and there is evidence that plastic nanoparticles can be absorbed by organisms and cross the blood‐brain‐barrier (BBB). However, their toxic effects, especially on the nervous system, have not yet been extensively investigated, and most of the knowledge is based on studies using different conditions and systems, thus hard to compare. In this work, physicochemical properties of non‐modified polystyrene (PS) and amine‐functionalized PS (PS‐NH2) nanoparticles are initially characterized. Advantage of a multisystemic approach is then taken to compare plastic nanoparticles effects in vitro, through cytotoxic readouts in mammalian cell culture, and in vivo, through behavioral readouts in the nematode Caenorhabditis elegans (C. elegans), a powerful 3R‐complying model organism for toxicology studies. In vitro experiments in neuroblastoma cells indicate a specific cytotoxic effect of PS‐NH2 particles, including a decreased neuronal differentiation and an increased Amyloid β (Aβ) secretion, a sensitive readout correlating with Alzheimer's disease pathology. In parallel, only in vivo treatments with PS‐NH2 particles affect C. elegans development, decrease lifespan, and reveal higher sensitivity of animals expressing human Aβ compared to wild‐type animals. In summary, the multisystemic approach discloses a neurotoxic effect induced by aminated polystyrene nanoparticles.

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Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-β Production by Altering Nicastrin Maturation and Intracellular Localization

Cited by 39 publications

References 78 publications

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

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

ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

A Multisystemic Approach Revealed Aminated Polystyrene Nanoparticles‐Induced Neurotoxicity

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