Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Synaptic Plasticity

Background:

• Synaptic dysfunction is a key feature of tauopathies, driving cognitive decline.
• Understanding synaptic vulnerability to tau pathology is crucial for developing effective treatments.
• Mechanisms of synaptic vulnerability in human tauopathies are not well understood.

Purpose of the Study:

• To investigate the vulnerability of human synapses to soluble tau oligomers (tauO).
• To determine the specific synaptic populations and cellular compartments targeted by tauO.
• To identify potential therapeutic targets for tauopathies by understanding tauO-synapse interactions.

Main Methods:

• Utilized post-mortem brain tissue from control and primary age-related tauopathy (PART) cases.
• Analyzed synaptosomes using western blotting, flow cytometry, and two-electrode voltage clamp recordings.
• Isolated and analyzed brain-derived tau oligomers (BDTO) interactomes via LC-MS/MS.

Main Results:

• Tau oligomers (tauO) preferentially bind to pre-synaptic terminals and synaptic vesicles.
• GABAergic synapses exhibit higher affinity for tauO, which potentiate GABAergic currents.
• Elevated tau aggregates in PART hippocampus correlate with a decreased excitatory/inhibitory ratio, indicating a pro-inhibitory shift.

Conclusions:

• This study provides direct evidence for selective synaptic vulnerability to tauO in human brain tissue.
• Findings highlight a preference for pre-synaptic and inhibitory synapses, challenging post-synaptic-focused therapies.
• Identifying pre-synaptic vesicle cycling as a tauO target necessitates tau therapeutics tailored to specific synaptic populations.