Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner.

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Amyloidogenic protein interactions are key drivers of neurodegenerative diseases.
• Codeposition of tau and amyloid-beta (Aβ) in Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) worsens outcomes.
• Molecular mechanisms of these heterotypic interactions remain challenging to elucidate.

Purpose of the Study:

• To investigate the direct interaction between Aβ and tau.
• To understand the role of tau fibril structure in Aβ nucleation and toxicity.

Main Methods:

• In vitro reconstruction of protein interactions.
• In vivo studies using transgenic models.
• Enzyme kinetics analysis of Aβ42 nucleation.
• Toxicity assays in neuroblastoma cells and C. elegans.

Main Results:

• AD and CTE tau fibrils catalyze Aβ42 primary nucleation in a fold-specific manner with enzyme-like kinetics.
• CTE fibrils showed the highest catalytic activity and templating effect on Aβ42.
• Tau fibrils enhanced Aβ42 toxicity in cellular and organismal models, dependent on tau fold.

Conclusions:

• Tau fibril structure dictates Aβ nucleation and toxicity, elucidating heterotypic interactions in proteinopathies.
• Amyloid structure and recognition mechanisms are critical determinants in disease progression.
• Findings provide a blueprint for designing therapeutics targeting specific amyloidogenic interactions.