The Relationship between p-tau217, p-tau231, and p-tau205 in the Human Brain Is Affected by the Cellular Environment and Alzheimer’s Disease Pathology

Abstract

The levels of p-tau217 and p-tau231 in cerebrospinal fluid (CSF) are associated with early amyloid beta (Aß) changes in the brain, while the CSF levels of p-tau205 are foremost related to tau pathology in the later stages of the disease. To investigate if the three p-tau variants are found to the same degree in different tau structures and if their co-localization is affected by the diagnosis and presence of Aß plaques, we immunostained sections of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) from non-demented controls (NC), patients with Alzheimer’s disease (AD), and primary age-related tauopathy (PART) against p-tau217, p-tau231, and p-tau205 together with Methoxi-X04. An analysis using confocal microscopy showed that the co-localization variable, the Pearson correlation coefficient (PCC), was significantly higher between p-tau231 and p-tau205 in neurofibrillary tangles compared to neuropil threads and dystrophic neurites in plaques. The PCC value between all three p-tau variants in the neuropil threads was significantly lower in the ECs of patients with AD compared to the NC and in the ITGs of patients with AD, with a high Aß load compared to PART. The lowered value was associated with proportionally higher amounts of non-colocalized p-tau231 and p-tau217 compared to p-tau205, and the PCC values were negatively correlated with Aß and the tangle loads in patients with AD, but positively correlated with tangles in PART. These results suggest that the proportion of and co-localization between p-tau217, p-tau231, and p-tau205 are dependent on cellular localization and are altered in response to AD pathology in a spatial–temporal manner.

The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

“…Consequently, there is still debate regarding the best marker for AD, and new candidates are continually being proposed ( Suárez-Calvet et al ., 2020 ; Karikari et al ., 2021 ; Salvadó et al ., 2024 ). Assessing the diversity of ptau isoforms in relation to AD pathology is challenging, as these isoforms appear at different stages of AD and exhibit heterogeneous relationships with amyloid plaques and neurofibrillary tangles ( Wennström et al ., 2024 ). For instance, an earlier study comparing phosphorylation at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199) in cerebrospinal fluid (CSF) showed that ptau181 could classify AD with Lewy body dementia better than p-tau231, which differentiated AD from frontotemporal dementia.…”