Venue: Centre Broca
Department of Neuroscience
Mayo Clinic – Florida, USA
Invited by Jean-Christophe Delpech (Inrae – NutrinNeuro)
Neuron-microglia interaction via extracellular vesicles in Alzheimer’s disease
Extracellular vesicles (EVs) carry pathogenic molecules and play a role in the disease spread, including aggregated tau proteins. The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery is responsible for the biogenesis of small EVs (exosomes), thus targeting critical ESCRT molecules can disrupt EV synthesis. We hypothesize that microgliaspecific targeting of ESCRT-I molecule Tsg101 suppresses EV-mediated propagation of tau pathology, leading to amelioration of the disease phenotype of the tauopathy mouse model. To test this hypothesis, we have studied microglia-specific deletion of Tsg101 in PS19 tau transgenic mice for the study. PS19 mice develop cognitive impairment as determined by Y-maze, forced alternation, novel object recognition and fear conditioning, which are reversed in PS19:Tsg101cKO mice. This is correlated with reduced Alz50+ tau accumulation, neurodegenerative microglial activation, neuroinflammation and complement pathway activation as determined by bulk RNA sequencing, ELISA, and neuropathology. Tsg101 cKO microglia show reduced expression of C3aR1 and CD68, and secretion of total and Tau+ EVs in vivo. Microglia-specific targeting of Tsg101 show beneficial effect for ameliorating the disease progression of tauopathy mouse model via suppression of EV secretion, microglial activation, tau accumulation and complement-dependent synaptic pruning. Microglial Tsg101 is a potential therapeutic target of Alzheimer’s disease and related tauopathy.