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Updated: Mar 11, 2026
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Tau acetylation at K331 has limited impact on tau pathology in vivo
Shoko Hashimoto1,2, Yukio Matsuba1,2, Mika Takahashi2
1Pioneering Research Division, Medical Innovation Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan.
Abstract:
Post-translational modifications regulate tau aggregation and propagation, yet how amyloid pathology shapes the tau modification landscape remains unclear. Using liquid chromatography-tandem mass spectrometry, we compared tau modifications in MAPT knock-in (MAPT KI) mice and MAPT/App double knock-in mice with AppNL-G-F amyloid pathology. Only subtle differences were detected, with a tendency toward increased acetylation within the repeat domain. Because K321 and K331 lie in the fibril-forming core, their roles were further examined. Acetylation at these sites was absent in cynomolgus monkey brains. To test functional relevance, we generated acetylation-mimicking MAPTK331Q knock-in mice on the MAPT KI background. Despite tau expression, these mice showed reduced tau phosphorylation at 24 months, with unchanged insoluble tau and seeding activity. Thus, K331 acetylation does not promote tau pathology.
Insights
Amyloid pathology minimally alters tau modifications, and K331 acetylation does not promote tau aggregation or seeding in mice. This research clarifies tau modification changes in Alzheimer's disease models.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Post-translational modifications critically regulate tau protein aggregation and propagation.
- The impact of amyloid pathology on the tau modification landscape remains incompletely understood.
Purpose of the Study:
- To investigate how amyloid pathology influences tau post-translational modifications.
- To determine the role of specific tau acetylation sites, particularly K321 and K331, in tau pathology.
Main Methods:
- Liquid chromatography-tandem mass spectrometry was employed to compare tau modifications in MAPT knock-in (KI) and MAPT/App double knock-in mice with amyloid pathology.
- Acetylation-mimicking MAPTK331Q KI mice were generated to assess functional relevance.
Main Results:
- Amyloid pathology induced only subtle changes in tau modifications, with a trend toward increased acetylation in the repeat domain.
- Acetylation at K321 and K331 was not detected in cynomolgus monkey brains.
- MAPTK331Q KI mice exhibited reduced tau phosphorylation but unchanged insoluble tau and seeding activity, indicating K331 acetylation does not promote tau pathology.
Conclusions:
- Amyloid pathology has a limited effect on the tau modification landscape.
- K331 acetylation does not appear to drive tau aggregation or seeding, challenging its role in promoting tau pathology.
