Abstract
Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-β, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation.
Highlights
Extracellular vesicles (EVs) constitute a heterogeneous group of specialized membranous vesicles involved in intercellular communication [1]
Compared to non-treated cells, expression of Gfap, Iba1, Cd11b, and p16 increased upon sEVold delivery, while iNOS was induced by both sEVold and sEVyoung (Figure 5). Due to their ability to transfer proteins and genetic information horizontally [18], EVs are increasingly recognized as a mediator of blood-brain communication and intercellular communication in the central nervous system (CNS) [19,20]
Misfolded proteins, disease-associated particles, such as α-synuclein, and prions can be transferred from origin to recipient cells via Small EVs (sEVs) driving the progression of neurodegenerative disorders, including Alzheimer’s disease [22]
Summary
Extracellular vesicles (EVs) constitute a heterogeneous group of specialized membranous vesicles involved in intercellular communication [1]. Small EVs (sEVs), known as exosomes, are formed intracellularly via endocytic invagination and are generated by outward budding at the endosomal membrane of the multivesicular bodies (MVBs) [2]. Neuroinflammation is characterized by glial activation and proinflammatory cytokine production by the central nervous system (CNS) resident cells [6]. Accumulating evidence implicates EVs in the aging process, e.g., plasma EV concentration decreases with age in humans. In this context, EVs from the elderly are preferentially taken up by B cells and monocytes [7]. Plasma EVs isolated from young donors but not from elderly donors promote the osteogenic differentiation of mesenchymal stem cells in a galectin-3-dependent manner [8]. EVs purified from the elderly suppress cell proliferation and osteogenic differentiation of bone marrow stromal cells [9]
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