Tags

Type your tag names separated by a space and hit enter

ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology.
J Neurosci. 2016 Mar 30; 36(13):3848-59.JN

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.

SIGNIFICANCE STATEMENT

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+Show Affiliations

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827.Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Lipid Metabolism Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and.Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, bu.guojun@mayo.edu kanekiyo.takahisa@mayo.edu.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, bu.guojun@mayo.edu kanekiyo.takahisa@mayo.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27030769

Citation

Sakae, Nobutaka, et al. "ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 36, no. 13, 2016, pp. 3848-59.
Sakae N, Liu CC, Shinohara M, et al. ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. J Neurosci. 2016;36(13):3848-59.
Sakae, N., Liu, C. C., Shinohara, M., Frisch-Daiello, J., Ma, L., Yamazaki, Y., Tachibana, M., Younkin, L., Kurti, A., Carrasquillo, M. M., Zou, F., Sevlever, D., Bisceglio, G., Gan, M., Fol, R., Knight, P., Wang, M., Han, X., Fryer, J. D., ... Kanekiyo, T. (2016). ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 36(13), 3848-59. https://doi.org/10.1523/JNEUROSCI.3757-15.2016
Sakae N, et al. ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. J Neurosci. 2016 Mar 30;36(13):3848-59. PubMed PMID: 27030769.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. AU - Sakae,Nobutaka, AU - Liu,Chia-Chen, AU - Shinohara,Mitsuru, AU - Frisch-Daiello,Jessica, AU - Ma,Li, AU - Yamazaki,Yu, AU - Tachibana,Masaya, AU - Younkin,Linda, AU - Kurti,Aishe, AU - Carrasquillo,Minerva M, AU - Zou,Fanggeng, AU - Sevlever,Daniel, AU - Bisceglio,Gina, AU - Gan,Ming, AU - Fol,Romain, AU - Knight,Patrick, AU - Wang,Miao, AU - Han,Xianlin, AU - Fryer,John D, AU - Fitzgerald,Michael L, AU - Ohyagi,Yasumasa, AU - Younkin,Steven G, AU - Bu,Guojun, AU - Kanekiyo,Takahisa, PY - 2015/10/13/received PY - 2016/02/22/accepted PY - 2016/4/1/entrez PY - 2016/4/1/pubmed PY - 2016/8/9/medline KW - ABCA7 KW - APP KW - BACE1 KW - cognitive function KW - lipid homeostasis KW - neuron SP - 3848 EP - 59 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 36 IS - 13 N2 - UNLABELLED: 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. SIGNIFICANCE STATEMENT: 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/27030769/ABCA7_Deficiency_Accelerates_Amyloid_β_Generation_and_Alzheimer's_Neuronal_Pathology_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=27030769 DB - PRIME DP - Unbound Medicine ER -