ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro

• Published in: Journal of neurochemistry 2008-07, Vol.106 (2), p.793-804
• Main Authors: Chan, Sharon L, Kim, Woojin Scott, Kwok, John B, Hill, Andrew F, Cappai, Roberto, Rye, Kerry-Anne, Garner, Brett
• Format: Article
• Language: English
• Subjects: ABC transporters; Adenosine triphosphatase; Adult and adolescent clinical studies; Alzheimer disease; Alzheimer’s disease; Amyloid beta-Peptides - pharmacology; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - classification; Amyloid Precursor Protein Secretases - metabolism; Animals; Apolipoproteins E - metabolism; ATP-Binding Cassette Transporters - physiology; ATP‐binding cassette transporters; Biochemistry; Biological and medical sciences; Biological Transport - drug effects; Cell Line, Transformed; Cellular biology; cholesterol; Cholesterol - metabolism; Cricetinae; Cricetulus; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Medical sciences; Neurology; Organic mental disorders. Neuropsychology; Peptide Fragments - pharmacology; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Transfection - methods; β-amyloid
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05433.x

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and, like its closest homolog ABCA1, belongs to the ABCA subfamily of full-length ABC transporters. ABCA1 promotes cellular cholesterol efflux to lipid-free apolipoprotein acceptors and also inhibits the production of neurotoxic β-amyloid (Aβ) peptides in vitro. The potential functions of ABCA7 in the brain are unknown. This study investigated the ability of ABCA7 to regulate cholesterol efflux to extracellular apolipoprotein acceptors and to modulate Aβ production. The transient expression of ABCA7 in human embryonic kidney cells significantly stimulated cholesterol efflux (fourfold) to apolipoprotein E (apoE) discoidal lipid complexes but not to lipid-free apoE or apoA-I. ABCA7 also significantly inhibited Aβ secretion from Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) or APP containing the Swedish K670M671[rightward arrow]N670L671 mutations when compared with mock-transfected cells. Studies with fluorogenic substrates indicated that ABCA7 had no impact on α-, β-, or γ-secretase activities. Live cell imaging of Chinese hamster ovary cells expressing APP-GFP indicated an apparent retention of APP in a perinuclear location in ABCA7 co-transfected cells. These studies indicate that ABCA7 has the capacity to stimulate cellular cholesterol efflux to apoE discs and regulate APP processing resulting in an inhibition of Aβ production.