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Role of Vitamin D and Antioxidant Functional Foods in the Prevention and Treatment of Alzheimer’s Disease Pathology
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
New tools for the study of the molecular pathways affected by this disease include genome-wide association studies and genetic sequencing. Some of the gene families being identified as relevant in disease pathogenesis by these methods include APOE, BIN1, CLU, and CD33. Involved biological pathways include immune response (ABCA7, CD33, CLU, CR1. HLA locus, MEF2C, PTK2B, TREM2), lipid metabolism (ABCA), and endocytosis (BIN1, CD2AP, EPHA1, PICAALM, SORL1) pathways (Verheijen & Sleegers, 2018).
Risk Factors for Dementia among Race and Ethnic Populations in the United States
Published in Gwen Yeo, Linda A. Gerdner, Dolores Gallagher-Thompson, Ethnicity and the Dementias, 2018
Several other candidate genes may play an important role in risk for African Americans, specifically. In genome wide meta-analyses of genetic risk factors for late onset AD among 5,896 African Americans from 12 datasets, 42 researches from the AD Genetics Consortium found that the strongest association was with the APOE gene, but there was also a strong association with ABCA7, a protein transporter gene previously found to have a weaker association with AD in European White populations (Reitz et al., 2013). The following other genetic factors were reported to be related to AD among African Americans in individual studies: SORL1 (Lee et al., 2007), TP73 (Li et al., 2004) and PVRL2 (Logue et al., 2011). A preliminary report suggests that CETP V405 valine homozygosity is associated with slower memory decline and lower risk for incident AD among African Americans (Sanders et al., 2010). However, a genetic risk score for AD based on the 10 most commonly found genetic loci was found to predict AD more weakly in non-Hispanic Blacks than among non-Hispanic Whites (Marden, Walter, Tchetgen Tchetgen, Kawachi, & Glymour, 2014).
Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
We previously demonstrated that A-SAA was produced by HASMC (3), however, the physiological role of A-SAA on cellular lipid metabolism in the vascular smooth muscle cells remains unclear. A-SAA seems to inhibit intracellular cholesterol synthesis in the vascular SMC (6). A-SAA also handles the formation of non-esterified cholesterol from esterified cholesterol in the foam cells via inhibited acylCoA transferase (ACAT) and enhanced neutral cholesterol esterase (NCE) activities (7), indicating that incubated SMC with A-SAA is in a preparatory state to release cholesterol-rich lipid particles by A-SAA. Lipid release by A-SAA in this study is consistent with a recent evidence that A-SAA released HDL particles from lineage cells and skin fibroblast via ABCA1 or ABCA7 molecules (8,9).
ABC transporters in breast cancer: their roles in multidrug resistance and beyond
Published in Journal of Drug Targeting, 2022
Anupama Modi, Dipayan Roy, Shailja Sharma, Jeewan Ram Vishnoi, Puneet Pareek, Poonam Elhence, Praveen Sharma, Purvi Purohit
ABC transporters can carry out both influx (moving substrates into cells) and efflux (moving substrates out of cells) functions. They are involved in the transport of inorganic anions, peptides and amino acids, sugars, hydrophobic compounds and metabolites across both the plasma membrane and intracellular membranes. Among the known ABC transporters, the ABCA subfamily is primarily involved in lipid trafficking in various organs and cell types [13]. While ABCA1 and ABCA7 take part in cholesterol efflux, ABCA3 and ABCA6 are implicated in MDR [14]. The ABCD subfamily of transporters is localised to peroxisomes (ABCD1-3) and lysosomes (ABCD4) [15]. The peroxisomal transporters help with the influx of long and very long-chain fatty acids and branched-chain acyl-CoA into peroxisomes. ABCD4 helps transport vitamin B12 out of lysosomes into the cytosol [15]. Other ABC transporters that are widely reported in the literature include ABCB subfamily member 1 (ABCB1, also known as multidrug resistance protein 1/MDR1/Permeability glycoprotein/P-glycoprotein/P-gp), ABCG subfamily member 2 (ABCG2, also known as breast cancer resistance protein/BCRP), and ABC subfamily C member 1 (ABCC1, also known as MDR-associated protein 1/MRP1) [16]. These efflux pumps are expressed in many human cancers including BC and are likely responsible for drug resistance. Although the clinical trials targeting ABCB1 have not yielded success, ABC transporters’ role in the development, progression and metastatic process surpass their functionalities in drug efflux [16].
An evidence-based review of neuronal cholesterol role in dementia and statins as a pharmacotherapy in reducing risk of dementia
Published in Expert Review of Neurotherapeutics, 2021
Siddhartha Dutta, Sayeeda Rahman, Rahnuma Ahmad, Tarun Kumar, Gitashree Dutta, Sudeshna Banerjee, Abdullahi Rabiu Abubakar, Adekunle Babajide Rowaiye, Sameer Dhingra, Velayutham Ravichandiran, Santosh Kumar, Paras Sharma, Mainul Haque, Jaykaran Charan
Another genetic risk factor for AD is ABCA7 (expressed highly in neurons and microglia [119]. A decreased level of ABCA7 has been noted in the AD brain [120,121]. One more study on the ABCA7 homolog in Drosophila implied that ABCA7 played a role in lipid transport from neuron to glial cells, thus protecting neurons’ function and viability from toxic peroxidized lipid accumulation [120]. Late-onset AD risk genes also include triggering receptors expressed on myeloid cells-2 (TREM2) and phospholipase C-2 (PLC 2) found expressed in microglia and play a role in lipid metabolism regulation. There is a 4-times increase in late-onset AD risk in carriers of R47H or R62H variant of TREM 2 [122–125]. TREM2 R47H variant reduces the binding ability of TREM2 to lipoprotein particles and causes alteration of microglial cholesterol load, and affects microglial phagocytosis of lipoprotein-bound Aβ [126].
The role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: a mechanistic review
Published in Expert Opinion on Therapeutic Targets, 2023
Tahere Paseban, Mohaddeseh Sadat Alavi, Leila Etemad, Ali Roohbakhsh
ABCB1 (P-glycoprotein) is an outwardly directed drug and lipid flippase (phospholipids and glycosphingolipids) that promotes multidrug resistance [199]. ABCB1 has also been implicated in Aβ efflux in BBB endothelial cells [85,200]. A collaboration between ABCB1 and LRP-1 make Aβ efflux across BBB possible (see Figure 2). In addition to ABCA1, ABCA7 is involved in cholesterol efflux and HDL formation [201]. However, previous studies have implicated a secondary role for ABCA7 in lipid transport compared to ABCA1. While ABCA7 makes small cholesterol-poor HDL particles, ABCA1 mostly produces big cholesterol-rich HDL particles [202]. In vitro and in vivo experiments showed that ABCA7 has a role in neuronal Aβ production and/or clearance [203,204]. Microglia and macrophages from ABCA7-KO mice exhibited substantial reductions in Aβ phagocytosis [205]. Also, ABCA7 polymorphisms have been associated with memory impairment in AD [206]. ABCG1 is another ABC superfamily member that transports intracellular cholesterol and sphingolipids to HDL [207]. Similar to ABCA1, cholesterol excess provokes ABCG1 expression [208]. ABCA1 and ABCG1 have a notable role in cholesterol efflux from macrophages and astrocytes. This process is overwhelmed during aging and is restored by LXR agonist administration [37]. Interestingly, ABCG1 and ABCG4 functions change γ-secretase distribution on the plasma membrane and decrease Aβ secretion [209]. Similar to ABCB1, ABCG4 effluxes Aβ from BBB into plasma [210]. Another transporter identified in the luminal plasma membrane of endothelial cells is ABCG2. It may contribute to the brain efflux of Aβ [211]. However, ABCG2’s exact role in Aβ elimination from the brain is debated [200]. Lipid homeostasis is regulated by more ABC members. ABCA3 is a transporter expressed in alveolar type II pneumocytes that excrete lung surfactant. ABCA3 transfers lipids into the lamellar bodies and its mutation causes fatal respiratory distress syndrome in the newborn [212]. ABCA12 is phylogenetically related to ABCA3 and participates in epidermal keratinocyte lamellar granule secretion. As a lipid transporter, this protein helps to form ceramides, but not phospholipids [213]. In patients with ABCA12 dysfunction (mainly due to mutations, harlequin-type ichthyosis), the lipid barrier on the skin is compromised, making them more susceptible to pathogens [214].