P‐tau235: a novel biomarker for staging preclinical Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p-tau) species such as p-tau217 and p-tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p-tau235 is a prominent feature of AD pathology. In addition, p-tau235 seemed to be preceded by p-tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p-tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p-235 increases early in AD continuum, and (ii) changes in CSF p-tau235 and p-tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p-tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.

Mass Spectrometry for Neurobiomarker Discovery: The Relevance of Post-Translational Modifications

“…Tau phosphopeptides pS191, pT217, pT231, pS262, pS262/T263, and pS289 showed a significant increase in AD compared with control samples [31]. Using an exploratory IP-MS approach, tau phosphorylation on brain soluble fraction was shown to reflect CSF, with pT181, pT217, and pT231 among the most prominent species identified in AD [110]. A doubly-phosphorylated tryptic peptide (pT231 + pS235) specific of AD brain was identified in higher amounts than the monophosphorylated (pT231) counterpart [110].…”

“…Using an exploratory IP-MS approach, tau phosphorylation on brain soluble fraction was shown to reflect CSF, with pT181, pT217, and pT231 among the most prominent species identified in AD [110]. A doubly-phosphorylated tryptic peptide (pT231 + pS235) specific of AD brain was identified in higher amounts than the monophosphorylated (pT231) counterpart [110]. Using sarkosyl-insoluble samples, Wesseling et al [70] performed a quantitative and qualitative tau protein profiling (FLEXITau and Q-Exactive MS) of 29 AD patients and 28 matched control individuals.…”

P301S‐hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau‐induced synaptic toxicities

“…Accumulating studies have revealed an initial role of hTau pathologies in neurodegenerative disease 8,9 . In P301S mutation cases, the mean age of clinical onset and death was reported as early as ∼34.3 and ∼40.8‐year old, respectively 10 .…”

“…[5][6][7] Accumulating studies have revealed an initial role of hTau pathologies in neurodegenerative disease. 8,9 In P301S mutation cases, the mean age of clinical onset and death was reported as early as ∼34.3 and ∼40.8-year old, respectively. 10 As clinical symptoms developed, the temporal atrophy rate was detectably increased in P301Scarried patients, followed by atrophy of the parietal and frontal lobes.…”

CSF p-tau231: A biomarker for early preclinical Alzheimer?

“… 6 Another p-tau epitope, CSF p-tau235, is significantly increased at the later phase of preclinical Alzheimer. 7 It needs to be investigated to what extent each of the p-tau epitopes provide different information on the disease and what they may be more useful for, both in clinical practice and in research settings.…”