ABCA7 deficiency accelerates amyloid-βgeneration and alzheimer’s neuronal pathology

Nobutaka Sakae, Chia-Chen Liu, Mitsuru Shinohara, Jessica Frisch-Daiello, Li Ma, Yu Yamazaki, Masaya Tachibana, Linda Younkin, Aishe Kurti, Minerva M Carrasquillo, Fanggeng Zou, Daniel Sevlever, Gina Bisceglio, Ming Gan, Romain Fol, Patrick Knight, Miao Wang, Xianlin Han, John D. Fryer, Michael L. FitzgeraldYasumasa Ohyagi, Steven G Younkin, Guojun D Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 in APP, PS1, or PS2 cause early-onset familial AD, ABCA7 encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which its loss-of-function variants 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 vivo microdialysis 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.

Original languageEnglish (US)
Pages (from-to)3848-3859
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number13
DOIs
StatePublished - Mar 30 2016

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Amyloid beta-Protein Precursor
Amyloid
Pathology
Alzheimer Disease
Brain
Neurons
Amyloid Precursor Protein Secretases
Knockout Mice
Sterol Regulatory Element Binding Protein 2
Eukaryotic Initiation Factor-2
Lipids
Endoplasmic Reticulum Stress
ATP-Binding Cassette Transporters
Microdialysis
Microglia
Endoplasmic Reticulum
Protein Kinases
Phosphotransferases
Phosphorylation
Peptides

Keywords

  • ABCA7
  • APP
  • BACE1
  • Cognitive function
  • Lipid homeostasis
  • Neuron

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

ABCA7 deficiency accelerates amyloid-βgeneration and alzheimer’s neuronal pathology. / Sakae, Nobutaka; Liu, Chia-Chen; Shinohara, Mitsuru; Frisch-Daiello, Jessica; Ma, Li; Yamazaki, Yu; Tachibana, Masaya; Younkin, Linda; Kurti, Aishe; Carrasquillo, Minerva M; Zou, Fanggeng; Sevlever, Daniel; Bisceglio, Gina; Gan, Ming; Fol, Romain; Knight, Patrick; Wang, Miao; Han, Xianlin; Fryer, John D.; Fitzgerald, Michael L.; Ohyagi, Yasumasa; Younkin, Steven G; Bu, Guojun D; Kanekiyo, Takahisa.

In: Journal of Neuroscience, Vol. 36, No. 13, 30.03.2016, p. 3848-3859.

Research output: Contribution to journalArticle

Sakae, N, Liu, C-C, Shinohara, M, Frisch-Daiello, J, Ma, L, Yamazaki, Y, Tachibana, M, Younkin, L, Kurti, A, Carrasquillo, MM, Zou, F, Sevlever, D, Bisceglio, G, Gan, M, Fol, R, Knight, P, Wang, M, Han, X, Fryer, JD, Fitzgerald, ML, Ohyagi, Y, Younkin, SG, Bu, GD & Kanekiyo, T 2016, 'ABCA7 deficiency accelerates amyloid-βgeneration and alzheimer’s neuronal pathology', Journal of Neuroscience, vol. 36, no. 13, pp. 3848-3859. https://doi.org/10.1523/JNEUROSCI.3757-15.2016
Sakae, Nobutaka ; Liu, Chia-Chen ; Shinohara, Mitsuru ; Frisch-Daiello, Jessica ; Ma, Li ; Yamazaki, Yu ; Tachibana, Masaya ; Younkin, Linda ; Kurti, Aishe ; Carrasquillo, Minerva M ; Zou, Fanggeng ; Sevlever, Daniel ; Bisceglio, Gina ; Gan, Ming ; Fol, Romain ; Knight, Patrick ; Wang, Miao ; Han, Xianlin ; Fryer, John D. ; Fitzgerald, Michael L. ; Ohyagi, Yasumasa ; Younkin, Steven G ; Bu, Guojun D ; Kanekiyo, Takahisa. / ABCA7 deficiency accelerates amyloid-βgeneration and alzheimer’s neuronal pathology. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 13. pp. 3848-3859.
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AU - Kurti, Aishe

AU - Carrasquillo, Minerva M

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AU - Wang, Miao

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