Fig. 13.

a Internalization processes and endocytic trafficking of brain-derived sEVs in microglia (1) and astrocytes (2). Brain-derived sEVs are taken up by both glial cell types; however, microglia demonstrate a more efficient internalization rate compared to astrocytes. Both cell types utilize the actin-dependent pathways, macropinocytosis (i) and/or phagocytosis (ii), for the transfer of sEVs within the cells and subsequently target them to the endolysosomal pathway (iii, iv) for further processing. Cholesterol depletion (v) induces sEV internalization in both microglia and astrocytes, possibly through induction of macropinocytosis (vi), exhibiting though a differential impact on sEV endosomal trafficking between the two cell types (vii). Cholesterol’s contribution to the interplay between endosomal recycling to the plasma membrane and/or lysosomal sorting requires further investigation (viii). b. sEV-dependent α-Syn transmission in microglia. Fibrillar α-Syn-associated sEVs (PFFs + sEVs) (2) are internalized (iii), enter the endosomal pathway (EE and LE), and are targeted to the lysosome (iv) for subsequent degradation. In the absence of sEVs (1), α-Syn-PFFs fail to enter the endosomal pathway, accumulate in the cytoplasm (i), and are cleared from the cells, possibly through autophagy (ii) [79]