期刊
BRAIN
卷 144, 期 2, 页码 515-527出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awaa373
关键词
CSF; biomarkers; tau; microtubule binding region; Alzheimer's disease
资金
- National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) [R01NS095773]
- Foundation for Barnes-Jewish Hospital
- John and Linda Tracy Family
- Coins for Alzheimer's Research Trust
- Alzheimer's Association Research Fellowship
- NIH [R01NS065667, P01 AG03991, P50 AG05681, P01 AG026276, P30 NS048056]
The study analyzed MTBR-Tau species in Alzheimer's disease and control CSF using sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry. The species containing the region beginning at residue 243 were found to be highly correlated with tau PET and cognitive measures. This suggests that CSF level of tau species containing the upstream region of MTBR may serve as biomarkers to stage Alzheimer's disease and track the development of tau-directed therapeutics.
Tau is a microtubule associated protein in the brain that aggregates in Alzheimer's disease to form pathological tangles and neurites. Insoluble tau aggregates composed of the microtubule binding region (MTBR) of tau are highly associated with the cognitive and clinical symptoms of Alzheimer's disease. In contrast, levels of soluble forms of tau, such as CSF total tau and phosphorylated tau-181 and tau-217, increase prior to tau aggregation in Alzheimer's disease, but these biomarkers do not measure the MTBR of tau. Thus, how CSF MTBR-tau is altered in Alzheimer's disease remains unclear. In this study, we used sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry to analyse MTBR-tau species in Alzheimer's disease and control CSF. We quantified MTBR-tau-specific regions in the CSF and identified that species containing the region beginning at residue 243 were the most highly correlated with tau PET and cognitive measures. This finding suggests that CSF level of tau species containing the upstream region of MTBR may reflect changes in tau pathology that occur in Alzheimer's disease and could serve as biomarkers to stage Alzheimer's disease and track the development of tau-directed therapeutics.
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