Regional correlates of tau pathology and synaptic function in primary age-related tauopathy.

PART specimens showed hippocampal accumulation of aggregation-prone tau assemblies (oligomeric and PHF-tau) compared to the superior middle temporal gyrus.

• Autopsy-derived tissues from neuropathologically validated PART specimens were analyzed from two brain regions: hippocampus and superior middle temporal gyrus (SMTG).
• Tau species including monomers, oligomers, and paired helical filaments (PHFs) were quantified by western blot.
• PART is defined by hippocampal-restricted tau pathology in the absence of amyloid-β, making the hippocampus the expected site of tau accumulation.

Hippocampal oligomeric and PHF-tau levels were negatively correlated with the synaptic excitation-to-inhibition (sE/I) ratio in PART.

• Synaptic function was assessed by microtransplantation of synaptosomal membranes into Xenopus laevis oocytes followed by electrophysiological recordings.
• Glutamatergic (kainate-evoked AMPAR) and GABAergic (GABAAR) currents were recorded to calculate the sE/I ratio.
• Higher levels of aggregation-prone tau assemblies in the hippocampus were associated with a shift toward synaptic inhibition (lower sE/I ratio).
• This negative correlation was predominantly observed within the hippocampus rather than the superior middle temporal gyrus.

Brain-derived tau oligomer (BDTO) interactome proteins linked to reduced sE/I were enriched for pathways related to vesicle-mediated transport, synaptic endocytosis, and neurotransmitter receptor regulation.

• Proteomic and enrichment analyses of brain-derived tau oligomer interactomes from PART hippocampi were performed.
• Enriched pathways included vesicle-mediated transport, synaptic endocytosis, and neurotransmitter receptor regulation.
• These proteomic correlates implicate vesicle trafficking pathways as mediators of tau oligomer-associated alterations in synaptic function.
• The BDTO interactome analysis provided mechanistic insight into how tau oligomers may drive synaptic dysfunction in early-stage tauopathy.

The microtransplantation of synaptosomal membranes into Xenopus laevis oocytes successfully detected region-specific differences in synaptic excitation-inhibition balance in human autopsy tissue.

• This electrophysiological approach allowed functional assessment of human brain-derived synaptic membranes ex vivo.
• Both AMPAR-mediated (glutamatergic) and GABAAR-mediated (GABAergic) currents were measurable from autopsy-derived synaptosomal preparations.
• The method enabled calculation of the sE/I ratio as a functional readout of synaptic balance across brain regions.

PART offers a tractable model to investigate tau-specific effects on synaptic physiology independent of amyloid-β pathology.

• PART is defined by hippocampal-restricted tau pathology in the absence of amyloid-β.
• This model allows investigation of tau-specific contributions to synaptic dysfunction without confounding amyloid-β effects.
• Emerging studies implicate microtubule-associated protein tau as a key modulator of neuronal excitability and synaptic dysfunction in human tauopathies.