Method for detecting MTBR tau isotype and application thereof
A mass spectrometry, biological sample technology, applied in the detection of MTBR tau isoforms and the field of use
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Embodiment 1
[0207] Several sample processing methods were developed - the immunoprecipitation method (IP) for N-terminal tau and mid-domain tau described in Sato et al., 2018; the chemical extraction method (CX); and the combination of IP and CX methods to enrich The process of assembling MTBR tau (post-IP-CX). The CX and post-IP-CX methods were specifically developed for the detection and quantification of MTBR tau. An overview of these methods is provided in Figure 2.
[0208] Briefly, CSF (approximately 475 μL) was mixed with 15 A solution of N Tau-441 (2N4R) Uniform Labeled (about 10 μL of a 100 pg / μL solution, or about 5 μL of a 200 pg / μL solution) was mixed as an internal standard. N-terminal tau and mid-domain tau species were immunoprecipitated with Taul and HJ8.5 antibodies, then processed and trypsinized as previously described (Sato et al., 2018).
[0209] For the CX method, mix CSF (approximately 475 μL) with containing 15 A solution of N Tau-441 (2N4R) Uniform Labeled (ab...
Embodiment 2
[0214] In this example, CSF samples from two clinical cohorts (LOAD100 and LOAD60) of subjects with late-onset Alzheimer's disease were analyzed. The Clinical Dementia Rating (CDR) scores and amyloid status of the samples used in this analysis are provided in Tables 1 and 2. CSF samples (approximately 500 μl each) were processed by the post-IP-CX method and evaluated by mass spectrometry, as described in Example 1. As previously described (Patterson BW et al., Ann Neurol 2015, 78: 439–453), Measurement of CSF Aβ42 and Aβ40 immunoprecipitated from CSF by mass spectrometry. As previously described (Barthélemy, N.R. et al., Alz Res Therapy , 2020, 12: 26), pT217% was measured by mass spectrometry.
[0215] Cutoff values for CSF Aβ42 / 40 were calculated from PiB-PET SUVR results to determine amyloid status. Based on cutoff determined for PiB-PET SUVR >1.42 ( Ann Neurol 2016;80:379–387), for CSF Aβ42 / 40, (% sensitivity + % specificity) reached a maximum at 0.1389. Notabl...
Embodiment 3
[0225] In this example, the existence and potential utility of MTBR tau species as Alzheimer's disease biomarkers is described in detail. The results show the presence of a significant amount of mid-domain-independent MTBR tau in CSF - that is, tau species that have been cleaved near the center of the polypeptide sequence (eg, around amino acid 224 of tau-441), resulting in a lack of N-terminal and mid-domains C-terminal fragments of regions ("C-terminal residues"). Furthermore, distinct regions of CSF MTBR tau stage disease progression and are associated with tau aggregation within the brain in Alzheimer's disease. These findings provide new insights into the relationship between MTBR tau in the brain and CSF and support the use of CSF tau as a fluid biomarker for Alzheimer's disease.
[0226] Material: Two different cohorts of human brain samples - a discovery cohort and a validation cohort - were used in the experiments of this example. The discovery cohort contained po...
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