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Basic Science and Pathogenesis.

Shrinath Kadamangudi1, Laura Sanchez1, Agenor Limon1

  • 1University of Texas Medical Branch, Galveston, TX, USA.

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This study reveals that toxic tau oligomers (tauO) in human brain tissue preferentially target pre-synaptic and inhibitory synapses. These findings suggest new therapeutic strategies for tauopathies focusing on pre-synaptic mechanisms.

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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.