The role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: a mechanistic review

ABSTRACTABSTRACTIntroduction Cholesterol homeostasis is critical for normal brain function. It is tightly controlled by various biological elements. ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that effluxes cholesterol from cells, particularly astrocytes, into the extracellular space. The recent studies pertaining to ABCA1’s role in CNS disorders were included in this study.Areas covered In this comprehensive literature review, preclinical and human studies showed that ABCA1 has a significant role in the following diseases or disorders: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, neuropathy, anxiety, depression, psychosis, epilepsy, stroke, and brain ischemia and trauma.Expert opinion ABCA1 via modulating normal and aberrant brain functions such as apoptosis, phagocytosis, BBB leakage, neuroinflammation, amyloid β efflux, myelination, synaptogenesis, neurite outgrowth, and neurotransmission promotes beneficial effects in aforementioned diseases. ABCA1 is a key molecule in the CNS. By boosting its expression or function, some CNS disorders may be resolved. In preclinical studies, liver X receptor agonists have shown promise in treating CNS disorders via ABCA1 and apoE enhancement.Graphical abstractKEYWORDS: ABCA1neuroinflammationapoptosisAlzheimer’s diseaseneurological disordersstroke Article highlights ABCA1 is a key molecule involved in cholesterol homeostasisABCA1 plays a key role in AD preventionABCA1 promotes Aβ efflux across BBB via apoE lipidationABCA1 induces beneficial effects on traumatic brain injury and hemorrhageABCA1 has anti-inflammatory properties and prevents neurodegenerationClinical studies of LXR agonists revealed significant adverse effectsABCA1 activators are alternative therapeutics to LXR agonistsAbbreviations 27HC27-hydroxycholesterol2VO2-vessel occlusionHMG-CoAR3-hydroxy-3-methylglutaryl-coenzyme A reductaseARF6ADP-ribosylation factor 6ADAlzheimer’s diseaseAβAmyloid β peptideAPPamyloid precursor proteinapoA1apolipoprotein A1apoEapolipoprotein EAQP4aquaporin-4ABCA1ATP-binding cassette transporter family A member 1 BACE1 beta-secretase 1BBBblood-brain barrier BCECs brain capillary endothelial cellsCCL5C-C motif chemokine ligand 5CCR3C-C motif chemokine receptor 3CCR5C-C motif chemokine receptor 5CXCL12C-X-C motif chemokine ligand 12CSFcerebrospinal fluidCUMSchronic unpredictable mild stressc-MSScombined magnetic stimulation systemc-MCAOcontralateral middle cerebral artery occlusionCXCR4C-X-C chemokine receptor type 4 CYP cytochrome P450 DDT dichlorodiphenyltrichloroethaneDAdopamineDATdopamine transporterEAEExperimental autoimmune encephalomyelitiseNOSendothelial nitric oxide synthaseERK1/2extracellular signal-regulated kinaseFDAFood and Drug Administration GULP1 engulfment adapter phosphotyrosine-binding domain containing 1HSShigh shear stressHDLhigh-density lipoproteinHMGB1high-mobility group box-1 proteinHBMECshuman brain microvascular endothelial cellsHDHuntington’s diseaseIGF-1insulin-like growth factor 1siRNAinterfering RNAsILinterleukinISischemic strokeKOknockoutLPSlipopolysaccharideLRP-1lipoprotein-related protein-1LXRsliver X receptorsLTPlong-term potentiationMAPKmitogen-activated protein kinaseMDDmajor depressive disorderMMP9matrix metalloproteinase-9mrTBImild repetitive traumatic brain injuryMAOBmonoamine oxidase BMEGF10multiple EGF-like-domains 10MSmultiple nMBPmyelin basic proteinNOnitric oxideNOXNADPH oxidaseNMDAN-methyl-D-aspartateNF-κBnuclear factor κBOPCsoligodendrocyte progenitor cellsOGDoxygen-glucose deprivationPDParkinson’s diseasePRRspattern recognition receptorsPPARγsperoxisome proliferator-activated gamma receptorsPI3Kphosphoinositide 3-kinasePMP22peripheral myelin protein 22 PSD-95 postsynaptic density 95ROSreactive oxygen species rTMS repetitive transcranial magnetic stimulationRGCretinal ganglion cellRXRretinoid X receptorsIAsaccular intracranial aneurysmsSREBPssterol regulatory-element binding proteinsSAHsubarachnoid hemorrhageSYNsynaptophysin TBI traumatic brain injuryTLR4Toll-like receptor 4TNF-αtumor necrosis factor αα-synsynucleinVCAM1vascular cell adhesion molecule-1Declaration of InterestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe authors appreciate Mashhad University of Medical Sciences for financial support.