Elucidating the pathogenic mechanisms of AD brain-derived tau-containing extracellular vesicles: Highly transmissible and preferential propagation to GABAergic neurons

Extracellular vesicles (EVs) are highly transmissible and play critical roles in propagation of tau pathology although its mechanism remains elusive. Here, for the first time, we comprehensively characterized the pathogenic effect of human brain-derived EVs isolated from Alzheimers disease (AD), prodromal AD (pAD) and non-demented control (CTRL) cases. AD-EVs are significantly enriched in epitope-specific tau oligomers in comparison to pAD-EVs or CTRL-EVs as determined by dot-blot and atomic force microscopy. AD-EVs were more efficiently internalized by murine cortical neurons and transferred tau, and had higher aggregation potency than pAD-EVs and CTRL-EVs in vitro. Strikingly, the inoculation of AD-EVs or pAD-EVs containing 300 pg of tau into the outer molecular layer of the dentate gyrus (DG) in 18 months-old C57BL/6 mice induced tau propagation throughout the hippocampus in 4.5 months, whereas inoculation of the equal amount of tau from CTRL-EV or as the oligomer or fibril-enriched fraction from the same AD donor show little propagation as determined by the semiquantitative brain-wide immunohistochemistry using multiple anti-phosphor-tau (p-tau) antibodies. AD-EVs induced accumulation of tau in the hippocampal region as both oligomers and sarkosyl-insoluble forms. Unexpectedly, p-tau+ cells were mostly GAD67+ GABAergic neurons followed by GluR2/3+ excitatory mossy cells, indicating preferential EV-mediated tau propagation to GABAergic neurons. Whole cell patch clamp recording of Cornu Ammonis (CA1) pyramidal cells showed significant reduction in the amplitude of inhibitory post-synaptic current. This is accompanied by the reduction in GAD67+GABAergic neuronal puncta around CA1 pyramidal neurons and in c-fos+ GAD67+ GABAergic neurons in the CA1 regions, reconfirming the reduced interneuronal projections to the CA1. Our study posits a novel mechanism of brain-derived EVs in spreading pathological tau in hippocampal neurons therefore leading to their dysfunction.