Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Brain cells release extracellular vesicles (EVs) carrying Alzheimer's disease (AD) related proteins.
• Brain-derived EVs (BDEVs) contain tau, a protein implicated in AD pathology, and can transmit this pathology.
• Mechanisms of EV-mediated tau pathology remain largely uncharacterized.

Purpose of the Study:

• To identify and characterize tau-interacting proteins within human brain-derived EVs (BDEVs).
• To investigate the role of these tau interactors in EV-mediated tau pathology.
• To evaluate potential therapeutic targets for inhibiting tau propagation in AD.

Main Methods:

• Immuno-affinity purification of tau from BDEVs isolated from AD and control cases.
• Tandem mass-tag mass spectrometry to profile the tau interactome in BDEVs.
• Validation of protein-tau interactions and colocalization using Nanotemper Monolith and Nanoimager.
• Functional assessment of tau loading, EV uptake, and tau seeding after silencing interactors.
• In vivo testing of inhibitors against identified molecules for BDEV-mediated tau propagation.

Main Results:

• Identified 764 proteins in the BDEV-associated tau interactome; 65 were downregulated and 5 upregulated in AD BDEVs.
• Enriched tau-interacting proteins correlated positively with Braak stage, confirming direct binding and colocalization with tau in BDEVs.
• Silencing candidate molecules reduced tau loading into EVs, decreased EV uptake by neurons, and diminished tau seeding activity.
• In vivo administration of a neutralizing antibody against a key target reduced tau pathology in a mouse model.

Conclusions:

• Identified tau-interacting molecules are significantly enriched in AD BDEVs.
• Targeting these molecules curtails tau loading into EVs and subsequent neuronal uptake.
• These findings highlight novel therapeutic targets for halting tau pathology in AD and related tauopathies.