ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology
| Autor: | Xianlin Han, Masaya Tachibana, Miao Wang, Fanggeng Zou, Yu Yamazaki, Yasumasa Ohyagi, Nobutaka Sakae, Romain Fol, Aishe Kurti, Minerva M. Carrasquillo, Jessica L. Frisch-Daiello, Daniel Sevlever, Linda H. Younkin, Ming Gan, Gina Bisceglio, Steven G. Younkin, Guojun Bu, Chia Chen Liu, John D. Fryer, Li Ma, Takahisa Kanekiyo, Michael L. Fitzgerald, Mitsuru Shinohara, Patrick Knight |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Amyloid Eukaryotic Initiation Factor-2 Mice Transgenic Presenilin ABCA7 03 medical and health sciences Amyloid beta-Protein Precursor Mice 0302 clinical medicine Alzheimer Disease mental disorders medicine Amyloid precursor protein Presenilin-1 Animals Humans Protein kinase A Memory Disorders Amyloid beta-Peptides biology General Neuroscience P3 peptide Brain Articles medicine.disease Lipid Metabolism Cell biology Disease Models Animal 030104 developmental biology Gene Expression Regulation ABCA1 Immunology Mutation biology.protein ATP-Binding Cassette Transporters Female Alzheimer's disease 030217 neurology & neurosurgery Signal Transduction |
| Popis: | 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 STATEMENTGene 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. |
| Databáze: | OpenAIRE |
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