Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain

Abstract

Alzheimer's disease (AD) neuropathologic change is characterized by amyloid plaques and neurofibrillary tangles (NFTs) that consist of aggregated amyloid beta (Abeta) and hyperphosphorylated tau proteins (p-tau), respectively. Although the global relationship between Abeta and p-tau has been studied for decades, it is still unclear whether a regional correlation exists between Abeta and p-tau in the human brain. Recent studies in cerebrospinal fluid (CSF) have suggested that tau phosphorylation at specific sites such as T217 is modified at an early stage of AD when amyloid plaques become detectable. We applied biochemical and mass spectrometry methods in human brain samples with and without Abeta plaque pathology to measure site-specific phosphorylation occupancies in soluble and insoluble tau. Our quantitative results identified multiple residues specifically hyper-phosphorylated in AD, including at sites T111, T153, S184 (or S185), T205, S208, T217, S262, and S285 in brain soluble tau. In contrast, the most enriched phosphorylated residues in brain insoluble tau were T111,

Defined Tau Phosphospecies Differentially Inhibit Fast Axonal Transport Through Activation of Two Independent Signaling Pathways

“…It is important to note that a fourth phosphorylation site in tau, pS208, may also be recognized by the AT8 antibody (Malia et al, 2016 ). pS208 has been much less studied than the other sites of this epitope, but recent mass spectrometry articles have found evidence of phosphorylation at this site in AD (Barthélemy et al, 2019 ; Horie et al, 2020 ). Soluble, but not insoluble tau purified from AD brains was phosphorylated at S208, although to a lesser extent than S202 or T205 (Horie et al, 2020 ).…”

“…pS208 has been much less studied than the other sites of this epitope, but recent mass spectrometry articles have found evidence of phosphorylation at this site in AD (Barthélemy et al, 2019 ; Horie et al, 2020 ). Soluble, but not insoluble tau purified from AD brains was phosphorylated at S208, although to a lesser extent than S202 or T205 (Horie et al, 2020 ). Similar to pT205, pS208 could not be identified in soluble tau from control brain tissues, but low levels were detected in control CSF (Barthélemy et al, 2019 ; Horie et al, 2020 ).…”

“…Soluble, but not insoluble tau purified from AD brains was phosphorylated at S208, although to a lesser extent than S202 or T205 (Horie et al, 2020 ). Similar to pT205, pS208 could not be identified in soluble tau from control brain tissues, but low levels were detected in control CSF (Barthélemy et al, 2019 ; Horie et al, 2020 ). While phosphorylation at this site appears to occur at low frequency, it is known to affect tau aggregation properties in vitro (Despres et al, 2017 ) and could therefore also affect tau monomer conformation in such a way as to influence the activation of downstream signaling pathways.…”

Comparison of Common and Disease-Specific Post-translational Modifications of Pathological Tau Associated With a Wide Range of Tauopathies

“…This means that almost all 231Thr residues are phosphorylated. Recently, phosphorylated tau profiles in soluble brain fractions in AD have been reported (Dujardin et al, 2020;Horie et al, 2020). In one report, Thr111, Ser113, Thr153, Thr181, Ser199, Ser202, Thr205, The217, Thr231, Ser262, and Ser396, and in the other, Thr181, Ser198, Ser199, Ser202, Thr217, Thr231, Ser262, Ser400, Thr403, Ser404 were phosphorylated, but in our analysis, all of these sites except Thr153 and Ser205 were phosphorylated (Table 2 and Supplementary Table 3).…”

Proteomics Landscape of Alzheimer’s Disease

“…Previously known AD markers including Tau and amyloid-beta peptides have been identified across multiple mass-spectrometry-based proteomics studies and have been successfully developed into targeted assays for quantitation [ 44 , 45 , 46 , 47 ]. Multiple studies by Barthelemey et al and groups have studied tau phosphorylation in CSF, brain, and plasma and reported an association between site-specific changes in tau phosphorylation and evolution of stages of dominantly inherited Alzheimer’s disease [ 48 , 49 , 50 ]. Another large-scale analysis of the CSF from AD patients has identified a consistent glycolytic signature [ 51 ].…”