期刊
FRONTIERS IN AGING NEUROSCIENCE
卷 14, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnagi.2022.945875
关键词
selective detection; RT-QuIC; Alzheimer's disease; protein aggregation; tau isoforms
资金
- Alzheimer's Association
- Biomarkers Across Neurodegenerative Diseases (BAND) Program
- Commonwealth of Virginia's Alzheimer's and Related Diseases Research Award Fund [BAND-19-614848]
- Commonwealth Health Research Board of Virginia [16-1, 18-4]
- Diabetes Action Research and Education Foundation
- Duke/NCCU CTSI Collaborative Research Award
- National Institute of Health
- Case Western Reserve University Alzheimer's Disease Research Center [AG061531, AG067607, NS109532, NS112010, AG051085]
- Duke/UNC Alzheimer's Disease Research Center [P30 AG062428]
- Owens Family Foundation [P30 AG072958]
- Alzheimer's Association
- Cure Alzheimer's Fund
- Biomarkers Across Neurodegenerative Diseases (BAND) Program
- Commonwealth of Virginia's Alzheimer's and Related Diseases Research Award Fund
- Commonwealth Health Research Board of Virginia [BAND-19-614848]
- Diabetes Action Research and Education Foundation [16-1, 18-4]
- Duke/NCCU CTSI Collaborative Research Award
- National Institute of Health
- Case Western Reserve University Alzheimer's Disease Research Center
- Duke/UNC Alzheimer's Disease Research Center [AG061531, AG067607, NS109532, NS112010, AG051085]
- Owens Family Foundation [P30 AG062428]
- Cure Alzheimer's Fund [P30 AG072958]
Tau aggregates, present in various tauopathies, have been identified as potential sources for selective detection and biomarker discovery. This study utilized different methods to investigate the role and seeding properties of tau aggregates in different diseases, and demonstrated the species-specific seeding ability of tau aggregates on human tau isoforms. These findings offer potential new biomarkers for the diagnosis of Alzheimer's disease and related tauopathies, and provide new insights into isoform-specific tau aggregation.
Tau aggregates are present in multiple neurodegenerative diseases known as tauopathies, including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions. To develop selective markers for AD and related rare tauopathies, we first used an engineered tau protein fragment 4RCF as the substrate for ultrasensitive real-time quaking-induced conversion analyses (RT-QuIC). We showed that misfolded tau from diseased AD and other tauopathy brains were able to seed recombinant 4RCF substrate. We further expanded to use six individual recombinant tau isoforms as substrates to amplify misfolded tau seeds from AD brains. We demonstrated, for the first time to our knowledge, that misfolded tau from the postmortem AD brain tissues was able to specifically seed all six full-length human tau isoforms. Our results demonstrated that RT-QuIC analysis can discriminate AD and other tauopathies from non-AD normal controls. We further uncovered that 3R-tau isoforms displayed significantly faster aggregation kinetics than their 4R-tau counterparts under conditions of both no seeding and seeding with AD brain homogenates. In summary, our work offers potential new avenues of misfolded tau detection as potential biomarkers for diagnosis of AD and related tauopathies and provides new insights into isoform-specific human tau aggregation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据