Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Tuesday Speaker Abstracts

CORRELATING CLATHRIN STRUCTURES WITH ENDOCYTIC DEFECTS IN ALZHEIMER'S DISEASE Lila Gordon 1 ; Justin Taraska 1,2 ; 1 National Institute of Health, NHLBI, Bethesda, DC, USA 2 Brown University, Providence, RI, USA Alzheimer’s Disease causes cognitive decline in millions of people every year. In the 1990s, scientists identified an isoform of the lipid transporter Apolipoprotein E (APOE) that correlates with increased risk of late-onset Alzheimer’s Disease (LOAD). Later, other studies showed that mutations in endocytosis-related genes also correlate with LOAD risk. To synthesize these genetic risk factors, our collaborator showed that cells expressing the LOAD-associated APOE isoform (E4) display functional endocytic defects. One key form of endocytosis is clathrin mediated endocytosis (CME). Through the present collaboration, we aim to explore structural differences in clathrin between disease genotype cells and healthy cells. Astrocytes, the most prevalent cell type in the central nervous system, also produce the most APOE. For this project, we use human iPSC-derived astrocytes. I do platinum replica electron microscopy (PREM) on unroofed cells from the healthy and disease astrocytes. Unroofing allows the user to expose the membrane of cells. Combining this method with PREM allows for the 3D visualization of structures at the membrane. After imaging, I quantify the shapes and sizes of clathrin structures. E4 astrocytes show significantly smaller dome: flat and sphere: dome ratios, which means that highly curved structures occupy a smaller proportion of total structures in those cells. This finding complements the observed reduction in endocytosis, implying that this defect may be clathrin-mediated and is taking place at the plasma membrane. Future directions include identifying structural underpinnings for rescue conditions. The functional data shows that expressing clathrin adaptor proteins rescue the endocytic defect. Additionally, I plan to examine clathrin lifetime for these cells given a probable explanation for an overall comparable amount of clathrin but differences in structure class is clathrin residency time at the membrane. Overall, this method of quantifying structural differences in disease-state versus wild-type presents a landscape of opportunities for examining cellular communication in disease.

15