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Aging-Associated Pro-inflammatory Shifts in Protein Corona Impact Pharmacokinetics

ABSTRACT: Here, we reveal that age-associated shifts in plasma composition remodel the protein corona of liposomes, leading to divergent biodistribution and immune responses. Using plasma from young (1-month), middle-aged (9-month), and aged (18-month) mice, we demonstrate that liposomes incubated in aged plasma acquire coronas enriched with immunoglobulins, particularly IgG. This age-dependent IgG enrichment enhances macrophage uptake via Fc receptor-mediated endocytosis and amplifies complement activation through the alternative pathway, triggering NF-κB signaling and a pro-inflammatory cascade marked by M1 macrophage polarization.

ORGANISM(S): Mus Musculus

SUBMITTER: Jigang Wang

PROVIDER: PXD062504 | iProX | Wed Apr 02 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:Extracellular vesicles (EVs) have several functions in the brain, serving as a mode of intercellular communication and as a pathway for disposal of cellular debris. While these functions serve to maintain healthy brain function, they may also contribute to diseases affecting the brain. EVs also change with aging of the brain, as levels of some EV subtypes increase at advanced ages in mice. These changes could be caused by aging-related changes such as inflammation, cellular senescence, or impairment of autophagy or mitochondrial function. Aging-related changes in brain EVs might also further aging-related changes, as levels of EVs in plasma may change with age and contribute to aging-related changes in inflammation and cellular metabolism. However, the effects of aging on brain EVs and the potential contribution of EVs to aging-related changes in the brain are not well understood. To address this question, we investigated the levels and protein contents of EVs isolated from brains of 4-, 12-, and 22-month–old C57Bl/6J mice. We detected no changes in EV levels, but observed age-dependent changes in EV proteins. EV fractions from aged (22-month–old) mice contained higher levels of extracellular matrix proteins than EV fractions from young (4-month–old) mice, with similar trends occurring in 12-month–old mice. Specifically, levels of hyaluronan and proteoglycan link proteins (Hapln) 1 and 2 were elevated in EV fractions from aged mice, as were levels of several chondroitin sulfate proteoglycans (CSPGs), which interact with Hapln1 and 2. Analysis of extracellular matrix in several brain regions of aged mice revealed increased immunolabeling for aggrecan, but an overall reduction in labeling with Wisteria floribunda agglutinin, which binds to chondroitin sulfate. These data are consistent with prior studies showing changes to the composition of extracellular matrix in aged brains, which might contribute to age-related cognitive decline. These findings reveal a novel association of EVs with changes in the extracellular matrix of the aging brain.

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Aging-Associated Pro-inflammatory Shifts in Protein Corona Impact Pharmacokinetics

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