Brain-derived tau oligomer polymorphs: distinct aggregations, stability profiles, and biological activities

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Microtubule-associated tau protein aggregation is a hallmark of neurodegenerative diseases like Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP).
• Tau oligomers are implicated as the primary neurotoxic species initiating aggregation and propagating prion-like structures.
• Distinct structural characteristics, termed polymorphs, differentiate aggregated tau in various diseases.

Purpose of the Study:

• To investigate the structural and functional differences of amplified brain-derived tau oligomers (aBDTOs) from AD, DLB, and PSP.
• To understand how these structural variations impact neuronal function, gene regulation, and disease progression.

Main Methods:

• Amplification of brain-derived tau oligomers (aBDTOs) from AD, DLB, and PSP patient samples.
• Structural and morphological characterization of the amplified tau oligomers.
• Functional assays assessing impact on neuronal function and gene regulation.

Main Results:

• Amplified brain-derived tau oligomers (aBDTOs) exhibit distinct structural and morphological features depending on the disease of origin (AD, DLB, PSP).
• These structural differences in tau oligomers significantly impact neuronal function and gene regulation.
• The observed variations correlate with disease progression and may explain different clinical phenotypes.

Conclusions:

• Distinct tau oligomeric polymorphs contribute to the unique clinical presentations and progression patterns of neurodegenerative diseases.
• Understanding these specific tau structures is crucial for elucidating disease mechanisms.
• Targeting specific neurotoxic tau polymorphs offers a potential avenue for developing personalized therapeutic strategies.