期刊
NEURAL REGENERATION RESEARCH
卷 14, 期 4, 页码 658-665出版社
WOLTERS KLUWER MEDKNOW PUBLICATIONS
DOI: 10.4103/1673-5374.247469
关键词
nerve regeneration; Alzheimer's disease; beta-amyloid precursor protein; amyloid beta; APP mutations; liquid chromatography-tandem mass chromatography; cellular localization; long A beta; neural regeneration
资金
- National Natural Science Foundation of China [81671268]
- Ministry of Science and Technology of China [2013YQ03059514]
- Key Laboratory for Neurodegenerative Disease of Ministry of Education of China [2015SJBX05, 2015SJZS01]
Alzheimer's disease is pathologically defined by accumulation of extracellular amyloid-beta (A beta). Approximately 25 mutations in beta-amyloid precursor protein (APP) are pathogenic and cause autosomal dominant Alzheimer's disease. To date, the mechanism underlying the effect of APP mutation on A beta generation is unclear. Therefore, investigating the mechanism of APP mutation on Alzheimer's disease may help understanding of disease pathogenesis. Thus, APP mutations (A673T, A673V, E682K, E693G, and E693Q) were transiently co-transfected into human embryonic kidney cells. Western blot assay was used to detect expression levels of APP, beta-secretase 1, and presenilin 1 in cells. Enzyme-linked immunosorbent assay was performed to determine A beta(1-40 )and A beta(1-42) levels. Liquid chromatography-tandem mass chromatography was used to examine VVIAT, FLF, ITL, VIV, IAT, VIT, TVI, and VVIA peptide levels. Immunofluorescence staining was performed to measure APP and early endosome antigen 1 immunoreactivity. Our results show that the protective A673T mutation decreases A beta(42)/A beta(40) rate by downregulating IAT and upregulating VVIA levels. Pathogenic A673V, E682K, and E693Q mutations promote A beta(42)/A beta(40) rate by increasing levels of CTF99, A beta(42), A beta(40), and IAT, and decreasing VVIA levels. Pathogenic E693G mutation shows no significant change in A beta(42)/A beta(40) ratio because of inhibition of gamma-secretase activity. APP mutations can change location from the cell surface to early endosomes. Our findings confirm that certain APP mutations accelerate A beta generation by affecting the long A beta cleavage pathway and increasing A beta(42/40) rate, thereby resulting in Alzheimer's disease.
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