Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in...

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Tau protein is central to microtubule dynamics and Alzheimer's disease (AD) pathogenesis.
• Post-translational modifications (PTMs) significantly influence tau's biological activity.
• Tissue transglutaminase (TG) and spermidine (SPD) levels are elevated in AD, suggesting a role in tau pathology.

Purpose of the Study:

• To investigate the effects of spermidine (SPD) polyamination on tau protein.
• To explore how SPD modification impacts tau's interaction with microtubules (MTs) and its aggregation propensity.
• To understand the role of SPD-modified tau in adopting pathogenic conformations relevant to AD.

Main Methods:

• Production of recombinant SPD-modified tau, with modifications primarily on N-terminal glutamine residues.
• Microtubule (MT) binding and polymerization assays to assess tau-MT interactions.
• Biochemical and biophysical assays to evaluate tau aggregation and conformational changes.

Main Results:

• SPD polyamination did not significantly alter tau's binding to MTs but enhanced MT polymerization kinetics.
• SPD-modified tau showed reduced polymerization into filamentous, beta-sheet-rich aggregates.
• SPD modification promoted the formation of pathogenic tau conformations, including oligomers and misfolded species.

Conclusions:

• SPD polyamination of tau enhances microtubule polymerization.
• This modification favors pathogenic tau conformations while inhibiting the formation of stable filamentous aggregates in vitro.
• Understanding SPD's role in tau modification may reveal novel therapeutic targets for Alzheimer's disease.