Internalization of external tau aggregates co-localize with early endocytic markers and lysosomes

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau protein aggregation and internalization are key drivers of Alzheimer's disease and tauopathies.
• Brain surveillance cells, including macrophages, are involved in clearing tau aggregates.
• The blood-brain barrier (BBB) can be compromised, allowing tau aggregate dissemination.

Purpose of the Study:

• To investigate the interaction of tau aggregates with a semi-permeable membrane (DOPC).
• To assess the impact of tau aggregates on neuronal cell integrity.
• To explore the cellular mechanisms macrophages use for tau aggregate clearance.

Main Methods:

• Nano-indentation was used to study the interaction between tau monomers/aggregates and DOPC.
• N2a cells were incubated with tau aggregates to evaluate cellular effects.
• Raw 264.7 mouse macrophages were cultured with tau aggregates and analyzed for co-localization with cellular markers.

Main Results:

• Tau monomers and the 4R domain interacted differently with DOPC, increasing critical force without disruption.
• Incubation with tau aggregates decreased axon-like structures and compromised N2a cell integrity.
• Tau 4R aggregates co-localized with Rab5 and Lamp1 in macrophages, indicating lysosomal involvement in clearance.

Conclusions:

• Tau aggregates can affect membrane integrity and neuronal cell structure.
• Macrophages employ lysosomal pathways for the clearance of tau aggregates.
• Understanding these interactions is crucial for developing therapeutic strategies for tauopathies.