Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau are key in Alzheimer's disease (AD).
• Tau pathology spreads via prion-like mechanisms, originating in specific brain regions and progressing over time.
• In AD, tau loses its N- and C-termini, potentially driving self-aggregation and disease progression.

Purpose of the Study:

• To investigate the role of tau termini deletion in tau aggregation and proteopathic properties.
• To determine if truncated tau can induce tau pathology in vitro and in vivo.

Main Methods:

• Generated a truncated tau protein (tau_151-391) lacking N- and C-termini.
• Induced tau aggregation using ultracentrifugation and overexpressed in HEK-293T cells.
• Assessed phosphorylation and proteopathic properties in vitro and in vivo.

Main Results:

• Truncated tau (tau_151-391) formed aggregates in cells and mouse brains, unlike full-length tau.
• Aggregated tau_151-391 was hyperphosphorylated and partially resistant to proteinase K digestion.
• Tau_151-391 aggregates induced further tau aggregation and hyperphosphorylation in cells and mouse brains.

Conclusions:

• Deletion of tau's N- and C-termini promotes aggregation and confers proteopathic characteristics.
• Tau_151-391 aggregates are potent inducers of tau aggregation and site-specific hyperphosphorylation.