APOE4 and INPP5D converge on membrane mechanics to regulate endocytosis in human astrocytes
Gevorgyan, A. S.; Gordon, L. M.; Combs, C. A.; Lita, A.; Yang, L. G.; Cuni Lopez, C.; Root, J. T.; Larion, M.; Taraska, J. W.; Narayan, P. S.
Show abstract
Disrupted endocytosis is an early feature of Alzheimers disease (AD), but how genetic risk factors functionally impact this pathway remains unclear. Using isogenic human iPSC-derived astrocytes, we show that the AD risk variant, APOE4, impairs clathrin-mediated membrane curvature, clathrin-mediated endocytosis, and alters plasma membrane lipid saturation and tension. Compared to APOE3 astrocytes, APOE4 cells display an accumulation of flat clathrin structures, reduced maturation of clathrin-coated pits, decreased early endosomes, and reduced endocytic uptake. We then identify the AD risk gene INPP5D as a modifier that restores early endocytosis in APOE4 astrocytes by promoting clathrin curvature and maturation through a mechanism distinct from membrane tension regulation. Beyond effects on trafficking, INPP5D overexpression also reduces lipid droplet accumulation and attenuates inflammatory signaling, linking membrane dynamics to disease-associated astrocytic phenotypes. Together, these findings establish altered membrane mechanics as a proximal consequence of the APOE4 variant and identify endocytosis as a common node linking AD risk genes.
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