Gordon, L. M. | bioRxiv Science

bioRxiv2026

APOE4 and INPP5D converge on membrane mechanics to regulate endocytosis in human astrocytes

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.

cell biology↗

bioRxiv2023

Metagenomics for pathogen detection during a wildlife mortality event in songbirds

Mass mortality events in wildlife can be indications of an emerging infectious disease. During the spring and summer of 2021, hundreds of dead passerines were reported across the eastern US. Birds exhibited a range of clinical signs including swollen conjunctiva, ocular discharge, ataxia, and nystagmus. As part of the diagnostic investigation, high-throughput metagenomic next-generation sequencing was performed across three molecular laboratories on samples from affected birds. Many potentially pathogenic microbes were detected, with bacteria comprising the largest proportion; however, no singular agent was consistently identified, with many of the detected microbes also found in unaffected (control) birds, and thus considered to be subclinical infections. Congruent results across laboratories have helped drive further investigation into alternative causes including environmental contaminants and nutritional deficiencies. This work highlights the utility of metagenomic approaches in investigations of emerging diseases and provides a framework for future wildlife mortality events. Article Summary LineThe causative agent of a mass mortality event in passerines remains inconclusive after metagenomic high-throughput sequencing with results prompting further investigation into non-pathogenic causes.

genomics↗