Distinct Conformations, Aggregation and Cellular Internalization of Different Tau Strains.

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Inter-cellular propagation of tau aggregates is a hallmark of neurodegenerative diseases.
• Tauopathies exhibit strain specificity in tau propagation, but the structural basis is unclear.
• Frontotemporal dementia (FTD) mutations may influence tau conformation and cellular behavior.

Purpose of the Study:

• To investigate how FTD-associated mutations (V337M, N279K) affect the aggregation, conformation, and cellular internalization of the tau four-repeat domain (K18).
• To compare the properties of mutated tau K18 variants with wild-type (WT) tau K18.

Main Methods:

• Combined structural and cell biological approaches.
• Heparin-induced and native-state aggregation experiments.
• Cellular uptake studies using SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived neurons.

Main Results:

• FTD tau-K18 variants (V337M, N279K) formed distinct soluble and fibrillar aggregates compared to WT tau.
• Oligomers of FTD tau-K18 variants showed significantly higher cellular uptake than WT tau-K18.
• Internalized tau oligomers localized in the cytoplasm, nucleus, neurites, and soma, co-localizing with endogenous tau and nucleolin.

Conclusions:

• Disease-associated tau mutations induce conformational and aggregation differences.
• These structural changes enhance tau's cellular internalization potency.
• Findings provide insights into the molecular pathogenesis of tauopathies involving mutated tau.