Specificity of ABCA7-mediated cell lipid efflux

Picataggi, Antonino; Rodrigues, Amrith; Cromley, Debra; Wang, Hu; Wiener, Joel P.; Garliyev, Viktor; Billheimer, Jeffrey T.; Grabiner, Brian C; Hurt, Jessica A.; Chen, Allen C.; Han, Xianlin; Rader, Daniel J.; Praticò, Domenico; Lyssenko, Nicholas N.

doi:10.1016/j.bbalip.2022.159157

Cited by 13 publications

(17 citation statements)

References 50 publications

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“…The drug transporters ABCB1, ABCC1, and ABCG2 were demonstrated to directly clear amyloid-β (Aβ) and to be dysfunctional in AD brains [ 174 , 175 ]. Furthermore, the lipid transporters ABCA1 and ABCA7 were shown to affect Aβ production, degradation, and clearance through yet unknown mechanisms [ 165 , 176 , 177 , 178 ]. Given the neurotoxic effects of Aβ as well as muHTT and other poly-glutamine deposits, and considering the neuroprotective nature of ABC transporters, a contribution of these transporters to the pathogenesis of HD should be investigated.…”

Section: Discussionmentioning

confidence: 99%

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

Möhle

Brüning

et al. 2022

IJMS

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Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD.

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Section: Discussionmentioning

confidence: 99%

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

Möhle

Brüning

et al. 2022

IJMS

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“…ABCA7 is part of the adenosine triphosphate–binding cassette (ABC) reporter family, important in regulating phospholipid and cholesterol transport across the cell membrane and within the cell between subcellular organelles ( 19 ). The transporter has also been shown to have a higher preference for transporting phosphatidylserine lipids relative to phosphatidylcholines out of the cell when compared with ABCA1 ( 25 ), suggesting the transporter has an important role in maintaining and regulating intracellular phosphatidylserine concentrations. ABCA7 is highly expressed in microglia in cell culture and neuronal cells, particularly in the hippocampus ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…In our putative mechanism, we rationalize this with a reduction in the flux of lipids through ABCA7. (2) ABCA7 has more affinity to export phosphatidylserines (PSs) than phosphatidylcholines (PCs) across the plasma membrane compared with other ABCA lipid transporters (e.g., ABCA1) ( 25 ). With a reduction in the function of ABCA7, intracellular concentrations of PSs increase relative to PCs.…”

Section: Discussionmentioning

confidence: 99%

Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

Dehghan

Pinto

Karaman

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 ( P = 5.0 × 10 −5 to 1.3 × 10 −44 ). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) ( P = 0.049–1.4 × 10 −5 ), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

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“…Similarly to ABCA1, ABCA7 plays a role in export of cholesterol and phospholipids to acceptor molecules such as ApoA‐I 14–18 . ABCA7 was also suggested to regulate efflux of cholesterol across the blood‐brain barrier (BBB) and to the cerebrospinal fluid, through transfer to acceptor molecules, although further studies are needed to confirm these findings 107,108 . Moreover, ABCA7 has been suggested to play a role in lipid flipping and can, therefore, change the local membrane lipid environment (Figure 4).…”

Section: Abca7 Functionmentioning

confidence: 99%

The ABC's of Alzheimer risk gene ABCA7

Duchateau,

Wawrzyniak,

Sleegers

2024

Alzheimer's & Dementia

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Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7’s identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode‐of‐action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain.Highlights Alzheimer's risk‐increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

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Specificity of ABCA7-mediated cell lipid efflux

Cited by 13 publications

References 50 publications

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

The ABC's of Alzheimer risk gene ABCA7

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