Yuzhi Wang, United States of America
Boston University PharmacologyAuthor Of 1 Presentation
ALZHEIMER’S DISEASE BRAIN-DERIVED EXTRACELLULAR VESICLES SPREAD TAU PATHOLOGY IN INTERNEURONS
Abstract
Aims
We hypothesize that tau-containing exosomes derived from Alzheimer’s affected human brains can serve as a seed for the spread of tauopathy in recipient animal brains.
Methods
Exosome-enriched fractions were isolated from unfixed frozen human brain samples from Alzheimer’s disease (AD) and control (CTRL) cases, as well as from tau knockout (TKO) mouse brains. Tau oligomer epitopes were determined by dot blot using multiple oligomeric antibodies. EVs were further examinedthe atomic force microscopy (AFM), and the efficiency for the neuronal uptake in vitro. Moreover, aged C57BL/6 mice were inoculated with human brain exosomes containing tau, comparing with the fibril or oligomeric tau, into the right dorsal hippocampus. After injection, the brains were incubated for 18 weeks. The brains were then subjected to immunohistochemistry for phosphorylated-tau (p-tau) epitopes.
Results
The inoculation of AD or prodromal AD extracellular vesicles (EVs) containing only 300 pg of tau into the OML of the DG resulted in the accumulation of abnormally phosphorylated tau by 4.5 months, whereas inoculation of an equal amount of tau from control EVs, isolated tau oligomers, or fibrils showed little tau pathology. Unexpectedly, phosphorylated tau was primarily accumulated in GABAergic interneurons and, to a lesser extent, GluR 2/3-positive excitatory mossy cells, showing preferential EV-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents.
Conclusions
This is the first time comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived EVs isolated from AD, prodromal AD, and non-demented control cases.