Wild Type and Tangier Disease ABCA1 Mutants Modulate Cellular Amyloid-β Production Independent of Cholesterol Efflux Activity

Article type: Research Article

Authors: Kim, Woojin S.^{a; b} | Hill, Andrew F.^{c; d} | Fitzgerald, Michael L.^e | Freeman, Mason W.^{e; f} | Evin, Genevieve^{d; g} | Garner, Brett^{h; i; *}

Affiliations: [a] Neuroscience Research Australia, Sydney, NSW, Australia | [b] School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia | [c] Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, VIC, Australia | [d] Mental Health Research Institute of Victoria, VIC, Australia | [e] Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [f] Department of Medicine, Massachusetts General Hospital, Boston, MA, USA | [g] Department of Pathology, University of Melbourne, VIC, Australia | [h] Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong NSW, Australia | [i] School of Biological Sciences, University of Wollongong, Wollongong NSW, Australia

Correspondence: [*] Correspondence to: Prof. Brett Garner, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia. Tel.: +61 2 4298 1576; Fax: +61 2 4221 8130; E-mail: [email protected].

Abstract: Cerebral amyloid-β (Aβ) deposition is a critical feature of Alzheimer's disease. Aβ is derived from the amyloid-β protein precursor (AβPP) via two sequential cleavages that are mediated by β-secretase and the γ-secretase complex. Such amyloidogenic AβPP processing occurs in lipid raft microdomains of cell membranes and it is thought that modulating the distribution of lipids in rafts may regulate AβPP processing and Aβ production. Certain ATP-binding cassette (ABC) transporters regulate lipid transport across cell membranes and, as recent studies reveal, within membrane microdomains. ABCA1 also regulates Aβ metabolism in the brain although its direct impact on AβPP remains an open question. Here we assessed the capacity of three ABCA1 mutants (that do not promote lipid efflux) to modulate AβPP processing. Unexpectedly, these non-functional mutants also reduced Aβ production similar to wild type ABCA1. ABCA1 expression did not alter AβPP localization in lipid rafts, and co-immunoprecipitation experiments indicated ABCA1 and AβPP physically interact. These data suggest that ABCA1 may regulate AβPP processing independent of its impact on membrane lipid homeostasis.

Keywords: ABCA1, AβPP processing, Alzheimer's disease, lipid transport, membrane biology, Tangier disease

DOI: 10.3233/JAD-2011-110521

Journal: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 441-452, 2011