title: ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing.
abstract: The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility.
authors.affiliation: From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, kanayo.sato@utoronto.ca.
authors.forename: Kanayo
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Abe-Dohmae
authors.affiliation: Nutritional Health Science Research Center, Chubu University, Matsumoto-cho 1200, Kasugai 487-8501, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada, and Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.affiliation: From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada, and.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D011992:Endosomes / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D034622:RNA Interference; D012307:Risk Factors
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; C485856:Abca7 protein, mouse; D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases
keywords: ABCA7; Alzheimer disease; amyloid precursor protein (APP); amyloid-β (Aβ); secretase; transgenic mice