An Enzyme-Generated Fragment of Tau Measured in Serum Shows an Inverse Correlation to Cognitive Function

Abstract

ObjectiveAlzheimer's disease (AD) is a devastating neurological disease characterized by pathological proteolytic cleavage of tau protein, which appears to initiate death of the neurons. The objective of this study was to investigate whether a proteolytic fragment of the tau protein could serve as blood-based biomarker of cognitive function in AD.MethodsWe developed a highly sensitive ELISA assay specifically detecting an A Disintegrin and Metalloproteinase 10 (ADAM10)-generated fragment of tau (Tau-A). We characterized the assay in detail with to respect specificity and reactivity in healthy human serum. We used samples from the Tg4510 tau transgenic mice, which over-express the tau mutant P301L and exhibit a tauopathy with similarities to that observed in AD. We used serum samples from 21 well-characterized Alzheimer's patients, and we correlated the Tau-A levels to cognitive function.ResultsThe Tau-A ELISA specifically detected the cleavage sequence at the N-terminus of a fragment of tau generated by ADAM10 with no cross-reactivity to intact tau or brain extracts. In brain extracts from Tg4510 mice compared to wt controls we found 10-fold higher levels of Tau-A (p<0.001), which indicates a pathological relevance of this marker. In serum from healthy individuals we found robust and reproducible levels of Tau-A, indicating that the analyte is present in serum. In serum from AD patients an inverse correlation (R2 = 0.46, p<0.001) between the cognitive assessment score (Mattis Dementia Rating Scale (MDRS)) and Tau-A levels was observed.ConclusionBased on the hypothesis that tau is cleaved proteolytically and then released into the blood, we here provide evidence for the presence of an ADAM10-generated tau fragment (Tau-A) in serum. In addition, the levels of Tau-A showed an inverse correlation to cognitive function, which could indicate that this marker is a serum marker with pathological relevance for AD.

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“…Serum tau is proteolytically cleaved, 148 and in patients with AD, levels of cleaved tau in CSF might correlate with cognitive function. 149 Tau levels in CSF and blood are elevated in boxers after a match, and CSF tau levels correlate with the quality and quantity of head impacts. 125,150 Recent evidence suggests that tau levels are elevated in the blood of ice hockey players after concussion, and may be useful in predicting recovery time.…”

Serum Tau Fragments Predict Return to Play in Concussed Professional Ice Hockey Players

“…In brief both assays are competitive ELISA assays. The Tau-A assay detects a neoepitope identified by LC-MS/MS as the amino acid sequence TPRGAAPPGQ, with an intra-assay coefficient of variation was 5.8% and an inter-assay CV% was 12.6% (Henriksen et al 2013). The Tau-C assay detects the caspase-3 generated cleavage site of Tau at Asp421 with an intra-assay CV% of 5.7% and an inter-assay CV% of 15% (Henriksen et al 2013;Henriksen et al 2014).…”

Alzheimer's disease — Recent biomarker developments in relation to updated diagnostic criteria

“…In addition, there are also studies in serum where an N-terminal fragment of tau is increased in patients with AD [113]. Together these studies in CSF, brain and serum suggest that tau is being enzymatically processed in an AD-associated manner.…”