A-Subclass ATP-Binding Cassette Proteins in Brain Lipid Homeostasis and Neurodegeneration

Abstract

The A-subclass of ATP-binding cassette (ABC) transporters comprises 12 structurally related members of the evolutionarily highly conserved superfamily of ABC transporters. ABCA transporters represent a subgroup of "full-size" multispan transporters of which several members have been shown to mediate the transport of a variety of physiologic lipid compounds across membrane barriers. The importance of ABCA transporters in human disease is documented by the observations that so far four members of this protein family (ABCA1, ABCA3, ABCA4, ABCA12) have been causatively linked to monogenetic disorders including familial high-density lipoprotein deficiency, neonatal surfactant deficiency, degenerative retinopathies, and congenital keratinization disorders. Recent research also point to a significant contribution of several A-subfamily ABC transporters to neurodegenerative diseases, in particular Alzheimer's disease (AD). This review will give a summary of our current knowledge of the A-subclass of ABC transporters with a special focus on brain lipid homeostasis and their involvement in AD.

Keywords: ATP-binding cassette transporter; Alzheimer’s disease.

Figure 1

Schematic view of an A-subclass ABC transporter. A-subclass ABC transporters are full-size transporters and consist of two transmembrane domains (TMD), which anchor the transporter into a lipid membrane (L), and two ATP-binding cassettes (ABC), at which two molecules ATP are bound and hydrolyzed to support the energy for substrate translocation between the inside (i) and outside (o) of a cell or compartment. A special feature of the A-subfamily members is the unusually large, first extracellular domain (ECD) of each TMD.

Figure 2

ABC transporters in apoE lipidation and Aβ metabolism. The ABCA1-apoE pathway of Aβ clearance hypothesis postulates that nascent apoE particles secreted from glial cells are initially lipidated by ABCA1 to form discoidal apoE-lipid particles. Further maturation and lipidation of these complexes by ABCG1 and presumably other ABC transporters finally results in mature, spherical apoE-containing lipoproteins. Both ABCA transporters and apoE have been implicated in the production, deposition, and clearance of Aβ. Knock-down and overexpression studies indicate that ABCA2 promotes Aβ production which is inhibited by ABCA1 and ABCA7. Amyloid formation is inhibited by ABCA1, and ApoE is required for Aβ deposition. ApoE also facilitates the cellular uptake of Aβ via apoE receptors and has a negative effect on Aβ clearance across the blood–brain barrier (Figure modified after Hirsch-Reinshagen et al., ; Hayashi, 2011).