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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein

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The acetylation of tau inhibits its function and promotes pathological tau aggregation

Todd J Cohen1, Jing L Guo, David E Hurtado

  • 1Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Nature Communications
|March 24, 2011
PubMed

Insights

Tau acetylation, particularly at K280, impairs neuronal function and promotes toxic tau aggregation in Alzheimer's disease (AD). This modification is linked to insoluble tau pathology, suggesting it as a therapeutic target for tauopathies.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Microtubule-associated protein tau stabilizes microtubules, crucial for neuronal survival.
  • Hyperphosphorylation of tau is implicated in Alzheimer's disease (AD) and tauopathies, leading to insoluble aggregates.
  • Other post-translational modifications of tau remain less understood in disease pathogenesis.

Purpose of the Study:

  • To investigate the role of tau acetylation in neuronal function and pathological aggregation.
  • To identify specific sites of tau acetylation and their impact on tau-microtubule interactions.
  • To explore the potential of acetylated tau as a biomarker and therapeutic target for AD and tauopathies.

Main Methods:

  • Mass spectrometry to identify acetylation sites on tau.
  • Biochemical and immunohistochemical analyses of tau transgenic mouse models and human AD brain tissues.
  • Assessment of tau-microtubule binding and aggregation.

Main Results:

  • Tau acetylation inhibits tau's microtubule-binding and stabilizing functions.
  • Lysine 280 (K280) within the microtubule-binding motif is a major site of tau acetylation.
  • Acetylated tau pathology specifically correlates with insoluble, Thioflavin-positive tau aggregates in diseased brains.

Conclusions:

  • Tau acetylation, especially at K280, impairs tau function and promotes pathological aggregation.
  • Acetylated tau is specifically detected in diseased brain tissue, suggesting a role in tau transformation.
  • Targeting tau K280 acetylation offers a potential strategy for drug discovery and biomarker development in AD and tauopathies.

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