title: ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology.
abstract: In Alzheimer's disease (AD), the accumulation and deposition of amyloid-β (Aβ) peptides in the brain is a central event. Aβ is cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase mainly in neurons. Although mutations inAPP,PS1, orPS2cause early-onset familial AD,ABCA7encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which itsloss-of-functionvariants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.In vivomicrodialysis studies indicated that the clearance rate of Aβ was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Aβ by increasing the levels of β-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). In the brains of APP/PS1;Abca7(-/-)mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis.
  
  
  CONCLUSIONS
  Gene variants inABCA7encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aβ deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aβ production by increasing the levels of β-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aβ clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Sakae
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frisch-Daiello
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Yu
authors.identifier: http://orcid.org/0000-0002-0806-4960
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tachibana
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Linda
authors.initials: L
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Aishe
authors.initials: A
authors.lastname: Kurti
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sevlever
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Gina
authors.initials: G
authors.lastname: Bisceglio
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Ming
authors.initials: M
authors.lastname: Gan
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Romain
authors.initials: R
authors.lastname: Fol
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0003-0813-8760
authors.initials: P
authors.lastname: Knight
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827.
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Lipid Metabolism Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.affiliation: Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, bu.guojun@mayo.edu kanekiyo.takahisa@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, bu.guojun@mayo.edu kanekiyo.takahisa@mayo.edu.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; C485856:Abca7 protein, mouse; C501918:Abce1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015852:Eukaryotic Initiation Factor-2; D053764:Presenilin-1
keywords: ABCA7; APP; BACE1; cognitive function; lipid homeostasis; neuron