Huentelman, M;
De Both, M;
Jepsen, W;
Piras, IS;
Talboom, JS;
Willeman, M;
Reiman, EM;
... Myers, AJ; + view all
(2019)
Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers.
Scientific Reports
, 9
, Article 9640. 10.1038/s41598-019-45896-4.
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Abstract
It was recently suggested that beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) functions as an amyloid beta (Aβ)-degrading enzyme; in addition to its better understood role as an APP secretase. Due to this finding we sought to understand the possible genetic risk contributed by the BACE2 locus to the development of late-onset Alzheimer's disease (AD). In this study, we report that common single nucleotide polymorphism (SNP) variation in BACE2 is associated with altered AD risk in apolipoprotein E gene (APOE) epsilon 4 variant (ε4) non-carriers. In addition, in ε4 non-carriers diagnosed with AD or mild cognitive impairment (MCI), SNPs within the BACE2 locus are associated with cerebrospinal fluid (CSF) levels of Aβ1-42. Further, SNP variants in BACE2 are also associated with BACE2 RNA expression levels suggesting a potential mechanism for the CSF Aβ1-42 findings. Lastly, overexpression of BACE2 in vitro resulted in decreased Aβ1-40 and Aβ1-42 fragments in a cell line model of Aβ production. These findings suggest that genetic variation at the BACE2 locus modifies AD risk for those individuals who don't carry the ε4 variant of APOE. Further, our data indicate that the biological mechanism associated with this altered risk is linked to amyloid generation or clearance possibly through BACE2 expression changes.
| Type: | Article |
|---|---|
| Title: | Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41598-019-45896-4 |
| Publisher version: | https://doi.org/10.1038/s41598-019-45896-4 |
| Language: | English |
| Additional information: | © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creative commons.org/ licenses/by/4.0/. |
| Keywords: | amyloid, Alzheimer’s disease, SNP, genetics, APOE, BACE2 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10078355 |
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