Evaluation of the Effect of Cell Type-Specific Deletion of ESCRT Genes on the Spread of Tau Pathology

We propose to comprehensively examine the molecular machinery of biogenesis of extracellular vesicles such as exosomes and microvesicles among different brain cell types (neurons, microglia) in mouse models. Extracellular vesicles are membranous vesicles enclosed by a lipid bilayer and containing the cytosol of their cell of origin. There is a positive correlation between disease progression and neuron-derived exosomal amyloid beta peptide and tau protein in plasma from Alzheimer’s disease and prodromal AD patients. However, little is known about how exactly exosomes package and spread pathogenic tau in which neuronal cell types in the central nervous system. Our preliminary study suggests that two components of the canonical exosomal pathway—the ESCRT (Endosomal Sorting Complexes Required for Transport) pathway—are critical for neuronal exosome synthesis. We hypothesize that cell type-specific targeting of the ESCRT pathway will suppress the spread of tau pathology in the brain. We will create a novel mouse model to examine whether neuron and microglia-specific targeting of ESCRT-0 (Hgs) and ESCRT-1 (Tsg101) will halt tau propagation in vivo.

The project’s first efforts will test whether microglia and neuron-specific silencing of the ESCRT-0 or ESCRT-1 gene suppresses the spread of tau pathology in the mouse brain. Hgs and Tsg101 will be targeted specifically by Cre-mediated gene disruption in vivo.

The second efforts will evaluate the effect of cell type-specific suppression of ESCRT-0 and ESCRT-1 on exosome synthesis using human-induced pluripotent stem cell-derived neurons and microglia on the spread of tau in vitro.

The newly gained mechanistic and functional knowledge of exosomal pathways that may contribute to AD pathogenesis can help on the road to a cure.