O1‐01‐02: Tau Phosphorylation Rates Change From Brain to Cerebrospinal Fluid and Are Differentially Affected by Alzheimer Disease
Year: 2019
Type: article
Abstract: Abnormally phosphorylated tau aggregates are a core pathology of Alzheimer disease (AD) rising together with clinical symptoms. Elevated phosphorylated tau (p-tau) in AD cerebrospinal fluid (CSF) has been attributed to a passive released of hyperphosphorylated tau occurring during AD neurons death. However, recent studies suggest CSF tau is actively released from cells under physiological and pathological conditions. We hypothesized active release could also affect the pattern of tau phosphorylation. The purpose of this study is to compare tau phosphorylation abundance in soluble brain extracts vs CSF, and in normal vs AD CSF to evidence potential changes occurring during tau active secretion from neurons. We developed highly sensitive and specific mass spectrometry method using parallel reaction monitoring (PRM) to identify p-tau sites. This method enabled site-specific p-tau/tau rates measurements independent from absolute tau concentrations. Measurements were performed on sarkosyl-soluble tau from human brain lysates and CSF pools from participants with (n=5) and without AD (n=7) according to amyloid status. We detected more than 30 distinct phosphorylated tau sites in sarkosyl-soluble human brain lysate and 12 sites on truncated tau in CSF. Phosphorylation comparison evidenced pT205 and pS208, that are recognized by AT8 antibody and define Braak stages of brain tau aggregation, were not detected in brain soluble tau but were found in both normal and AD CSF. Phosphorylation rates comparison evidenced that active release of tau from soluble brain fraction to CSF modified the phosphorylation abundance in a site-specific manner. CSF tau from non-AD participants were significantly hyperphosphorylated at T111, T205, S208, T217 and T231. In AD CSF, hyperphosphorylation on these sites was exacerbated and phosphorylation on T153 and T175 were specifically detected. Inversely, we found S199 and S202 were hypophosphorylated in normal CSF compared to brain, and not hyperphosphorylated in AD CSF.
Source: Alzheimer s & Dementia
Institution: Washington University in St. Louis
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980812226