Abstract
BackgroundSoluble tau oligomers (tauO) are early, synaptotoxic drivers of dysfunction in tauopathies. While selective vulnerability is well documented at the cellular level, emerging evidence suggests that synaptic subtypes may differ in their susceptibility to tau pathology. Still, the key factors that shape synaptic vulnerability to toxic tauO, particularly in humans, remain poorly understood.ObjectiveTo define the synaptic compartments and subtypes most vulnerable to tauO and identify molecular correlates underlying this susceptibility.MethodsSynaptosomes were isolated from cognitively normal human autopsy specimens and acutely challenged with preformed recombinant tauO. Flow cytometry with multiplexed immunophenotyping resolved tauO engagement across intact pre- and postsynaptic compartments and excitatory versus inhibitory subtypes. Functional effects were assessed by microtransplanting synaptic membranes into Xenopus laevis oocytes and recording ligand-gated GABAergic and glutamatergic responses. Complementary LC-MS/MS proteomics of brain-derived tau oligomers (BDTO) from PBS-soluble hippocampal lysates of primary age-related tauopathy (PART) cases were analyzed using SynGO enrichment to identify molecular correlates.ResultsTauO preferentially engaged presynaptic compartments and showed elevated association with GABAergic synapses. Functionally, acute tauO exposure selectively enhanced GABA(A)R-mediated responses, with no effect on AMPAR-mediated currents. The PART BDTO interactome was enriched for presynaptic vesicle-associated proteins involved in vesicle cycling and neurotransmitter release, consistent with a presynaptic axis of vulnerability.ConclusionsThis integrative analysis identifies a compartment- and subtype-specific vulnerability of human synapses to tauO, highlighting a presynaptic inhibitory bias as a potential driver of synaptic dysfunction and tau propagation in early-stage tauopathies.