Compartment-Specific Lysosomal Heterogeneity in Microglia Is Regulated by Adaptor Protein Complex-4
Year: 2026
Type: preprint
Abstract: Microglia rely on lysosomes to clear phagocytosed material and orchestrate immune responses, but the mechanisms governing glial lysosome diversity and function remain largely undefined. Using high-resolution, high-throughput 3D imaging of mouse brain tissue, we find that glial lysosomes are heterogeneous in size and protease content depending on subcellular location. CD68+ and LAMP1+ vesicles were more numerous in glial processes than cell bodies; process LAMP1+ vesicles carried less protease than cell-body vesicles, but CD68+ protease content did not differ between compartments, revealing at least two lysosomal subpopulations within processes. Loss of Adaptor Protein complex 4 (AP-4) selectively remodels this landscape: it increases CD68+ vesicle number and CD68 enrichment, particularly in processes, without changing protease content, and disrupts the normal cell-body-versus-process pattern in protease- and CD68-enrichment. AP-4 loss also lowers protease content in cell-body LAMP1+ vesicles, mirroring a neuronal phenotype. These results provide the first evidence of glial lysosome heterogeneity and implicate AP-4 in shaping microglial lysosome composition and inflammatory function.
Authors: Elizabeth A. Somodji, Swetha Gowrishankar
Institution: University of Illinois Chicago
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Modulation of autophagic flux as a therapeutic strategy for Alzheimer's disease, Training program in the biology and translational research on Alzheimer's diseaseand related dementias, Modulation of autophagic flux as a therapeutic strategy for Alzheimer's disease, Elucidating the role of Adaptor Protein complex-4 in regulating axonal autophagic and lysosomal pathways
OpenAlex ID: W7213537109