We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, and ATP synthesis capacity in mice. As an extension of our previous study, we also found that proteins which comprise the blood-brain barrier (BBB) and regulate mitochondrial quality control were also significantly decreased in the mice's cortical MVs with aging. Interestingly, the neuroinflammatory protein fibrinogen (Fgn) was increased in mice brain MVs, which corresponds with clinical reports indicating that the plasma Fgn concentration increased progressively with aging. In this study, protein-protein interaction network analysis indicated that high expression of Fgn is linked with downregulated expression of both BBB- and mitochondrial fission/fusion-related proteins in mice cortical MVs with aging. To investigate the mechanism of Fgn action, we observed that 2 mg/mL or higher concentration of human plasma Fgn changed cell morphology, induced cytotoxicity, and increased BBB permeability in primary human brain microvascular endothelial cells (HBMECs). The BBB tight junction proteins were significantly decreased with increasing concentration of human plasma Fgn in primary HBMECs. Similarly, the expression of phosphorylated dynamin-related protein 1 (pDRP1) and other mitochondrial fission/fusion-related proteins were also significantly reduced in Fgn-treated HBMECs. Interestingly, DRP1 knockdown by shRNA(h) resulted in the reduction of both BBB- and mitochondrial fission/fusion-related proteins in HBMECs. Our results suggest that elevated Fgn downregulates DRP1, leading to mitochondrial-dependent endothelial and BBB dysfunction in the brain microvasculature. 

Fibrinogen in mice cerebral microvessels induces blood-brain barrier dysregulation with aging via a dynamin-related protein 1-dependent pathway.

Seminal extracellular vesicles (SemEVs) are repositories of biomolecules, including metabolites involved in the regulation of sperm function. The correlation between the metabolite profile of SemEVs and semen parameters, along with their role in regulating sperm function, is an unexplored area. This preliminary study evaluated the metabolomic content of SemEVs. Semen samples were obtained from 18 healthy men, and SemEVs were extracted from seminal plasma using the size exclusion chromatography qEV Gen 2-35 nm column coupled with an automatic fraction collector. The physical characterization of SemEVs was carried out with the ZetaView PMX-430-Z QUATT laser system. EV protein markers were detected using Western blot. In addition, these SemEVs were used for metabolomic profiling and functional bioinformatic analysis. The mean concentration of isolated SemEVs was 1.7 ± 1.1 × 10 

Untargeted Metabolomic Profiling of Extracellular Vesicles Isolated from Human Seminal Plasma

Background Antiretroviral therapy suppresses human immunodeficiency virus (HIV) replication; however, nearly 50% of HIV infected patients suffer from HIV-associated neurocognitive disorders (HAND). Recently, we reported that proteins in plasma circulating extracellular vesicles (EVs) of either simian human immunodeficiency virus (SHIV) infected rhesus macaques (RMs) or HIV-infected patients show a link to neuropathogenesis. In this study, we show that proteins in circulating EVs of SHIV-infected RMs (SHIV-EVs) were associated with dysregulation of the synaptic signaling pathway. Methods Plasma circulating EVs were isolated from SHIV-infected (SHIV-EVs) and uninfected (CTL-EVs) RMs and characterized by the ZetaView analyzer (n = 5/group) and transmission electron microscopy. Several EV-associated markers were detected by western blotting. Proteomic analysis of the isolated EVs (n = 3/group) was performed using liquid chromatography/mass spectrometry. Using ingenuity pathway analysis (IPA), the differentially expressed proteins (DEPs) involved in the dysregulation of different synaptic signaling pathways were assessed. Results Interestingly, proteins in SHIV-EVs were involved in synaptogenesis signaling deactivation, synaptic long-term potentiation/depression, and glutamate receptor signaling, as well as activation of semaphorin neuronal repulsive signaling pathways. Intriguingly, we observed that several proteins, which are involved in synaptic vesicle (SV) assembly and SV fusion, were abundantly under-expressed in SHIV-EVs compared with EVs of uninfected RMs. Dysregulated proteins in SHIV-EVs show possible deactivation of (a) SV priming, docking, and fusion in presynaptic neurons; and (b) synaptic spine development/density and synapse stabilization in postsynaptic neurons. Conversely, the activation of semaphorin neuronal repulsive signaling pathway in SHIV-EVs showed possible activation of cytoskeleton contraction/rearrangement, microtubule stabilization, and action repulsion, as well as deactivation of microtubule polymerization and action generation/outgrowth in SHIV-infected RMs. Dysregulated synaptic signaling-related proteins in SHIV-EVs were involved in several neuropathology-related disorders/diseases, including early/progressive neurological disorder, cognitive impairment, degenerative dementia, and Alzheimer’s disease. Conclusions Our novel findings suggest that plasma circulating EVs can be a useful noninvasive technique to elucidate the mechanisms involved in the development of central nervous system dysfunction and the progression of neurological diseases such as HAND. Supplementary Information The online version contains supplementary material available at 10.1186/s12964-025-02464-w.

Plasma circulating extracellular vesicles reveal dysregulation of synaptic signaling in SHIV-infected rhesus macaque

Aging is an unavoidable stress with ever‐increasing detrimental effects on the brain microvasculature, which affects neuronal health/function and adds vulnerability to strokes and neurological diseases. In this study, we performed an extensive examination of proteins involved in the structure and function of mouse brain cortical microvessels (MVs) using a discovery‐based quantitative proteomic approach.

Effects of Aging on Proteome Dynamics in Mice Brain Microvessels: ROS Scavengers, mRNA/Protein Stability, Glycolytic Enzymes, Mitochondrial Complexes, and Basement Membrane Components

Combined antiretroviral therapy suppresses HIV replication, but 30‐60% of patients suffer from HIV‐1 associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in HIV CNS infection. Using proteomics, we investigated possible circulating exosomal protein links to neuropathogenesis in SIV‐infected rhesus macaque (RM).

Circulating Exosomal Proteins are linked to Neuropathogenesis in SIV‐infected Rhesus Macaque: A Proteomic Approach

Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50–60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in the central nervous system (CNS) due to HIV infection. We investigated links among circulating plasma exosomal (crExo) proteins and neuropathogenesis in simian/human immunodeficiency virus (SHIV)-infected rhesus macaques (RM) and HIV-infected and cART treated patients (Patient-Exo). Isolated EVs from SHIV-infected (SHIV-Exo) and uninfected (CTL-Exo) RM were predominantly exosomes (particle size < 150 nm). Proteomic analysis quantified 5654 proteins, of which 236 proteins (~4%) were significantly, differentially expressed (DE) between SHIV-/CTL-Exo. Interestingly, different CNS cell specific markers were abundantly expressed in crExo. Proteins involved in latent viral reactivation, neuroinflammation, neuropathology-associated interactive as well as signaling molecules were expressed at significantly higher levels in SHIV-Exo than CTL-Exo. However, proteins involved in mitochondrial biogenesis, ATP production, autophagy, endocytosis, exocytosis, and cytoskeleton organization were significantly less expressed in SHIV-Exo than CTL-Exo. Interestingly, proteins involved in oxidative stress, mitochondrial biogenesis, ATP production, and autophagy were significantly downregulated in primary human brain microvascular endothelial cells exposed with HIV+/cART+ Patient-Exo. We showed that Patient-Exo significantly increased blood–brain barrier permeability, possibly due to loss of platelet endothelial cell adhesion molecule-1 protein and actin cytoskeleton structure. Our novel findings suggest that circulating exosomal proteins expressed CNS cell markers—possibly associated with viral reactivation and neuropathogenesis—that may elucidate the etiology of HAND.

/pdf/circulating-plasma-exosomal-proteins-of-either-shiv-infected-138xx8kg.pdf

Circulating Plasma Exosomal Proteins of Either SHIV-Infected Rhesus Macaque or HIV-Infected Patient Indicates a Link to Neuropathogenesis

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Effects of Aging on Proteome Dynamics in Mice Brain Microvessels: ROS Scavengers, mRNA/Protein Stability, Glycolytic Enzymes, Mitochondrial Complexes, and Basement Membrane Components

Circulating Exosomal Proteins are linked to Neuropathogenesis in SIV‐infected Rhesus Macaque: A Proteomic Approach

Circulating Plasma Exosomal Proteins of Either SHIV-Infected Rhesus Macaque or HIV-Infected Patient Indicates a Link to Neuropathogenesis