期刊
CURRENT ALZHEIMER RESEARCH
卷 14, 期 6, 页码 578-585出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205014666170203093219
关键词
Alzheimer's Disease; ADAM10; alpha-secretase; apolipoprotein E; APOE; amyloid
资金
- National Institute of Neurological Disorders and Stroke (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS072026]
- National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- Arizona Department of Health Services (Arizona Alzheimer's Research Center) [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Roskamp Foundation
- National Institute on Aging of the National Institutes of Health [R01AG041971]
- Michael J. Fox Foundation for Parkinson's Research
Background: The APOE4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). It has been associated with an accumulation of amyloid-beta (A beta) in the brain, which is produced through the sequential cleavage of the amyloid-beta precursor protein (A beta PP) by beta- and gamma-secretases. Alternatively, A beta PP is also cleaved by alpha-secretases such as A Disintegrin and Metalloproteinase Domain-containing Protein 10 (ADAM10). Objective: While several studies have investigated the impact of apoE on beta- and gamma-secretase, interactions between apoE and a-secretases have not been fully examined. We investigated the effect of each apoE isoform on ADAM10 in vitro and in human cortex samples. Method: ADAM10 activity and kinetics was assessed in cell-free assays and the biological activity of ADAM10 further investigated in 7WCHO cells over-expressing wild type A beta PP through ELISA. Finally, ADAM10 expression and activity was observed in the soluble fraction of both control and Alzheimer's Disease human cortex samples through ELISA. Results: In a cell free assay, ADAM10 activity was found to be significantly lower in apoE4 samples compared to apoE2. 7WCHO cells over expressing wild type A beta PP exposed to apoE4 demonstrated reduced formation of sA beta PP alpha compared to other apoE isoforms. We also identified APOE and AD dependent changes in ADAM10 activity and expression in the soluble brain fraction of human brain cortex. Conclusion: Overall, our data demonstrates an apoE isoform-dependent effect on ADAM10 function and A beta PP processing which may describe the elevated amyloid levels in the brains of AD subjects carrying the APOE4 allele.
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