Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Prion-like protein aggregates, particularly Tau, drive neurodegenerative diseases like Alzheimer's disease (AD) and Tauopathies.
• Tau pathology spreads progressively, correlating with disease severity, and involves Tau preformed fibrils (PFFs) acting as seeds.
• Existing Tau receptors lack specificity for fibrillar Tau, and cellular mechanisms of Tau PFF spreading are not fully understood.

Purpose of the Study:

• To identify specific cell surface receptors mediating the uptake and spread of pathogenic Tau preformed fibrils (PFFs).
• To investigate the role of lymphocyte-activation gene 3 (Lag3) in Tau pathology propagation.
• To evaluate Lag3 as a potential therapeutic target for AD and Tauopathies.

Main Methods:

• Assessed binding of Lag3 to Tau PFFs versus monomeric Tau.
• Utilized primary cortical neurons with Lag3 deletion or inhibition to study Tau PFF internalization and propagation.
• Examined Tau pathology spread and behavioral deficits in Lag3-deficient mice following Tau PFF injection.

Main Results:

• Lymphocyte-activation gene 3 (Lag3) specifically binds to Tau PFFs, not monomeric Tau.
• Lag3 deletion or inhibition significantly reduced Tau PFF internalization, propagation, and neuron-to-neuron transmission.
• Mice lacking neuronal Lag3 showed attenuated Tau pathology and behavioral deficits after Tau PFF administration.

Conclusions:

• Neuronal Lag3 acts as a specific cell surface receptor for pathologic Tau.
• Lag3 mediates the internalization and spread of Tau PFFs in the brain.
• Lag3 represents a promising therapeutic target for Alzheimer's disease and related Tauopathies.