Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology

Abstract

To date, there is no validated fluid biomarker for tau pathology in Alzheimer’s disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer’s disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer’s disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer’s disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer’s disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer’s disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer’s disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer’s disease and other tauopathies.

Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

“…To test whether the alterations in soluble tau metabolism also involved a differential truncation of tau, we measured a C-terminally truncated variant of tau, ending at amino acid 368 (called Tau 368 ), which is enriched in NFT (23), using a recently described singlemolecule array assay (24). The results are shown in fig.…”

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg

“…In one study, N-terminal tau fragment truncated at 224 amino acids (N-224) colocalised to neurofibrillary tangles in brain extracts and showed significantly higher levels in CSF from patients with AD in comparison to controls, with higher baseline levels predictive of steeper cognitive decline [24]. More recently, tau N-368 has also been found to be significantly elevated in CSF of AD patients, with a ratio of tau N-368 to total tau exhibiting a strong negative correlation with tau PET [25]. AD pathology also significantly affects phosphorylation patterns, with hyperphosphorylation seen of a number CSF tau sites in comparison to healthy controls.…”

Significance of Blood and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: Sensitivity, Specificity and Potential for Clinical Use

“…Interestingly, the level of MC1 reactivity correlates with the severity and progression of AD. To our knowledge, no assay has been developed to detect this early marker of pathology in biofluids, likely due to the possibility that tau truncated species [ 205 , 206 , 207 , 208 ] could prevent the identification of a conformational tau epitope using the currently available immunoassays, which are-based primarily on mid-region-directed antibodies. We believe that, although this pathological feature is not per se easily “translatable”, it should be kept in consideration when designing and developing new tau biomarkers platforms.…”

“…The authors were able to demonstrate that mid-region- and N-terminal-containing fragments increase with disease, while full-length tau is just a small fraction of the tau present in both normal and AD CSF. A recent study has also shown that the ratio between C-terminally truncated tau368 and t-tau is significantly decreased in patients with Alzheimer’s disease, with a strong correlation with 18 F-GTP1 retention in brain [ 207 ] (a measure of tangle pathology in vivo); these data suggest that tau fragment may preferentially accumulate in tangles, and the CSF ratio tau368/t-tau reflects tangle pathology in brain and can be used as an additional tau biomarker to stage and improve the diagnosis of Alzheimer’s disease.…”