Poster #035, Sanford Burnham Prebys
Uncovering the Impact of SORL1 Variants on the Microglial Proteome in Alzheimer’s Disease
Mentor: Giau Vo, PhD
SORL1 encodes SORLA, an intracellular sorting receptor whose dysfunction is strongly associated with Alzheimer’s disease (AD). However, how distinct SORL1 variants reshape the microglial proteome and whether these effects depend on amyloid-β exposure remain unclear. Here, isogenic human embryonic stem cell-derived microglia-like cells (hMGLs) carrying a SORL1 knockout (R744X), the truncating variant E2055X, or the missense variant T2134M were compared with wild-type cells under basal conditions and following oligomeric amyloid-β (oAβ) exposure using label-free quantitative proteomics and confocal amyloid analysis. The SORL1 R744X produced the most extensive proteomic disruption, with four- to six-fold more differentially abundant proteins than E2055X or T2134M. Approximately 75% of KO (knockout)- associated changes were already present under basal conditions, whereas most changes associated with E2055X and T2134M emerged following oAβ exposure. These proteomic differences were not explained by the measured intracellular amyloid burden, which was comparable across genotypes under the conditions examined. The SORL1 R744X preferentially altered pathways related to inflammatory signaling, cell-cycle regulation, intracellular trafficking, lipid metabolism, interferon responses, and redox homeostasis. Despite their distinct proteomic profiles, all three SORL1 models showed coordinated alterations in extracellularmatrix-associated proteins. Together, these findings demonstrate that SORL1 dysfunction generates both shared and genotype-specific microglial proteomic states. Extracellular-matrix remodeling may represent a common response to SORL1 dysfunction, whereas the broader changes caused by SORL1 loss identify additional pathways for mechanistic and therapeutic investigation.