期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 13, 页码 3848-3859出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3757-15.2016
关键词
ABCA7; APP; BACE1; cognitive function; lipid homeostasis; neuron
资金
- Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program
- National Institutes of Health [R01AG18023, R01AG035355, R01AG027924, R01AG046205, RF1AG051504 01, P01NS074969, P50AG016574, R01HL074136, R01HL101274]
- Alzheimer's Association
- Cure Alzheimer's Fund
In Alzheimer's disease (AD), the accumulation and deposition of amyloid-beta (A beta) peptides in the brain is a central event. A beta is cleaved from amyloid precursor protein (APP) by beta-secretase and gamma-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 A beta was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to A beta by increasing the levels of beta-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 2 alpha (eIF2 alpha). 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.
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