title: Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer's disease.
abstract: ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and has been detected in macrophages, microglia, and neurons. ABCA7 promotes efflux of lipids from cells to apolipoproteins and can also regulate phagocytosis and modulate processing of amyloid precursor protein (APP) to generate the Alzheimer's disease (AD) amyloid-β (Aβ) peptide. Genome-wide association studies have indicated that ABCA7 single nucleotide polymorphisms confer increased risk for late-onset AD; however, the role that ABCA7 plays in the brain in the AD context is unknown. In the present study, we crossed ABCA7-deficient (A7(-/-)) mice with J20 amyloidogenic mice to address this issue. We show that ABCA7 loss doubled insoluble Aβ levels and thioflavine-S-positive plaques in the brain. This was not related to changes in APP processing (assessed by analysis of full-length APP and the APP β C-terminal fragment). Apolipoprotein E regulates cerebral Aβ homeostasis and plaque load; however, the apolipoprotein E concentration was not altered by ABCA7 loss. Spatial reference memory was significantly impaired in both J20 and J20/A7(-/-) mice compared with wild-type mice; however, there were no cognitive differences between J20 and J20/A7(-/-) mice. There were also no major differences detected in hippocampal or plaque-associated microglial/macrophage markers between J20 and J20/A7(-/-) mice, whereas the capacity for bone marrow-derived macrophages derived from A7(-/-) mice to take up oligomeric Aβ was reduced by 51% compared with wild-type mice. Our results suggest that ABCA7 plays a role in the regulation of Aβ homeostasis in the brain and that this may be related to altered phagocyte function.
authors: Neuroscience Research Australia, Randwick, New South Wales 2031, Australia.
authors: Woojin S
authors: WS
authors: Kim
authors: Hongyun
authors: H
authors: Li
authors: Kalani
authors: K
authors: Ruberu
authors: Sharon
authors: S
authors: Chan
authors: David A
authors: DA
authors: Elliott
authors: Jac Kee
authors: JK
authors: Low
authors: David
authors: D
authors: Cheng
authors: Tim
authors: T
authors: Karl
authors: Brett
authors: B
authors: Garner
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency*; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D037502:Galectin 3 / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008569:Memory Disorders / Q000175:diagnosis / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011930:Reaction Time / Q000235:genetics
chemical_list: C545487:APP protein, human; D018528:ATP-Binding Cassette Transporters; C485856:Abca7 protein, mouse; C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; D037502:Galectin 3; D008840:Microfilament Proteins