Tau microtubule binding region in cerebrospinal fluid as a biomarker to differentiate tau pathology in Alzheimer’s disease

Authors: Kanta Horie, Nicolas R Barthelemy, Chihiro Sato, Randall J Bateman

Published: 2020-12-07

Abstract

AbstractBackgroundTau deposition in brain is a pathological hallmark of some neurodegenerative disorders including Alzheimer’s disease (AD). Braak staging of post‐mortem tissue suggests pathological tau spreads through the brain via synaptically connected pathways, and specific tau isoforms containing the microtubule binding region (MTBR) are thought to be essential to form extracellular seeds that propagate pathology. Tau is cleaved at the mid‐domain and the N‐ter to mid‐domain species are actively secreted extracellularly, whereas MTBR‐tau show faster turn‐over and deposition in brain. Recently, we identified the MTBR regions (residues 299‐317 (HVPG) and 354‐369 (IGSL)) and the nearby region (residue 243‐254 (LQTA)) were specifically enriched in AD brain aggregates. However, if and how these species change in extracellular spaces under pathophysiogical conditions were not known. This work describes the behavior of the pathological species in extracellular spaces by analyzing human cerebrospinal fluid (CSF) with changes of disease progression.MethodWe established a method to quantify MTBR‐tau in CSF, consisting of chemical extraction followed by tryptic digestion and mass spectrometry analysis. This method was applied to the CSF analysis of AD participants (n=50 amyloid negative with CDR=0‐1, n=50 amyloid positive with CDR=0‐2). A subset of these participants was followed longitudinally (2‐9 years).ResultOur method revealed that (1) MTBR‐tau were specifically increased in amyloid positive group and HVPG was the most significantly increased even in clinically asymptomatic stages, (2) the increases of HVPG and IGSL were saturated after symptomatic onset, whereas LQTA continued to increase even after the clinical onset, and (3) the concentration of LQTA showed the highest correlation with tau pathology as measured by positron emission tomography (PET) for tau (Pearson r=0.84, n=35) as well as cognitive testing measures.ConclusionMTBR‐tau enriched in AD brain aggregates are increased in AD CSF. These findings suggest HVPG and LQTA in CSF could be promising biomarkers to recapitulate amyloid status and tau pathology in AD, respectively. Notably, only LQTA showed the continuous increase along to disease progression in terms of tau‐PET as well as amyloid status and cognitive decline, which suggests the region is key to differentiate tau pathology in AD.