Uncovering elevated tau TPP motif phosphorylation in the brain of Alzheimer's disease patients

INTRODUCTION A wide array of post‐translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecula...

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Published in:Alzheimer's & dementia 2024-03, Vol.20 (3), p.1573-1585
Main Authors: Bellier, Jean‐Pierre, Cai, Yuqi, Alam, Sarah M., Wiederhold, Thorsten, Aiello, Arica, Vogelgsang, Jonathan S., Berretta, Sabina, Chhatwal, Jasmeer P., Selkoe, Dennis J., Liu, Lei
Format: Article
Language:English
Subjects:
Alzheimer's disease
Antibodies
Biological markers
Biomarkers
brain
Brain research
Demographics
Mutation
Neuropathology
Pathology
Phosphorylation
Regional differences
tau protein
Variability
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Summary:INTRODUCTION A wide array of post‐translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecular motif threonine‐proline‐proline (TPP). METHODS We validated new and existing antibodies against pT217, pT231, pT175, and pT181, then combined immunohistochemistry (IHC) and immunoassays (ELISA) to broadly examine the phosphorylation of the tau TPP motif in AD brains. RESULTS The tau burden, as examined by IHC and ELISA, correlates to Braak stages across all TPP sites. Moreover, we observed regional variability across four TPP motif phosphorylation sites in multiple brains of sporadic AD patients. DISCUSSION We conclude that there is an elevation of TPP tau phosphorylation in AD brains as disease advances. The regional variability of pTPP tau suggests that examining different phosphorylation sites is essential for a comprehensive assessment of tau pathology.
ISSN:1552-5260
1552-5279
1552-5279
DOI:10.1002/alz.13557