TY - JOUR
T1 - CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease
AU - Horie, Kanta
AU - Barthélemy, Nicolas R.
AU - Sato, Chihiro
AU - Bateman, Randall J.
N1 - Publisher Copyright:
© 2020 The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - CSF
KW - biomarkers
KW - microtubule binding region
KW - tau
UR - http://www.scopus.com/inward/record.url?scp=85102715235&partnerID=8YFLogxK
U2 - 10.1093/brain/awaa373
DO - 10.1093/brain/awaa373
M3 - Article
C2 - 33283854
AN - SCOPUS:85102715235
SN - 0006-8950
VL - 144
SP - 515
EP - 527
JO - Brain
JF - Brain
IS - 2
ER -