Extracellular Vesicle-Mediated Delivery of VEGF and NGF Protects Dopaminergic Neurons in 6-OHDA-Induced Parkinson's Disease Models.

Extracellular vesicles carrying the tenascin-C protein participate in glucose metabolism in neurodegenerative injury via inhibiting the AKT/GLUT1 pathway.

Extracellular vesicles (EVs) serve as key mediators of intercellular communication within the nervous system. An adequate glucose supply is essential for normal brain function; however, cerebral glucose metabolism is progressively impaired in Parkinson's disease (PD). Here, we show that EVs released by microglia exposed to 40 μM paraquat (PQ) are internalized by dopaminergic neurons, where they impair glucose metabolism and induce neurodegenerative injury through the intercellular transfer of tenascin-C (TNC). TNC, which has been proposed as a potential indicator of disease severity, is upregulated following neurological injury and has been implicated in neuronal apoptosis and neuroinflammation. EVs released by microglia exposed to 40 μM PQ reduced neuronal glucose uptake, disrupted glucose metabolism, and exacerbated mitochondrial dysfunction. Proteomic analysis revealed that EVs derived from PQ-exposed microglia were enriched in TNC. Co-immunoprecipitation analysis further demonstrated an interaction between EV-transferred TNC and protein kinase B (AKT) in recipient neurons. Both depletion of TNC from EVs and pharmacological activation of AKT restored glucose uptake in recipient neurons. Collectively, these findings demonstrate that, under PQ exposure, activated microglia impair neuronal glucose metabolism by releasing TNC-enriched EVs. The EV-mediated TNC-AKT/ glucose transporter 1 (GLUT1) axis may therefore contribute to PQ-induced dopaminergic neurotoxicity and represent a potential therapeutic target for PD.

NRG1β-overexpressing mesenchymal stem cell-derived exosomes alleviate oxygen-glucose deprivation-mediated neuronal injury via the miR-296-3p/MAOA axis

Background Cerebral ischemic injury is a severe neurological disorder necessitating effective therapeutic strategies. Neuregulin-1β (NRG1β) and microRNAs are critical for neuroprotection, but the mechanisms by which NRG1β regulates microRNAs in neuronal injury are not fully understood. Methods We characterized mesenchymal stem cells (MSCs) through their phenotypic markers and multilineage differentiation potential, confirming NRG1β overexpression in engineered MSCs. Transmission electron microscopy and nanoparticle tracking analysis were used to isolate and characterize exosomes. In vitro studies evaluated the effects of MSC/NRG1β-exosomes on OGD-treated HT-22 neuronal cells. Results Mesenchymal stem cells/NRG1β-exosomes significantly enhanced HT-22 neuronal survival while reducing apoptosis and reactive oxygen species (ROS). The treatment reduced oxidative stress by lowering malondialdehyde (MDA) levels and boosting superoxide dismutase (SOD) activity. It also inhibited inflammatory cytokines such as IL-1β, TNF-α, and IL-6. Studies conducted in vivo with a middle cerebral artery occlusion model demonstrated that MSC/NRG1β-exosomes led to a reduction in infarct size, enhanced histopathological results 24 h after injury. Mechanistically, these exosomes were enriched with miR-296-3p, targeting monoamine oxidase A (MAOA) for downregulation. Inhibition of miR-296-3p or MAOA overexpression negated the protective effects of MSC/NRG1β-exosomes. Conclusion Our findings demonstrate that exosomes derived from NRG1β-overexpressing mesenchymal stem cells (MSCs) exert neuroprotective effects against ischemic injury by upregulating miR-296-3p. This microRNA targets MAOA, leading to a reduction in apoptosis, oxidative stress, and inflammation. These results highlight the therapeutic potential of MSC/NRG1β-exosomes and the miR-296-3p/MAOA signaling axis in the treatment of ischemic brain injury.

Imaging the therapeutic effects of cerebral endothelial cell derived exosome treatment of a preclinical model of Alzheimer’s disease

Background Alzheimer’s disease (AD) is characterized by the excessive accumulation of select proteins in the brain, associated with altered vascular function, glymphatic transport, cerebrospinal fluid (CSF) dynamics, and cerebral microstructure. Exosomes derived from cerebral endothelial cells (CEC-Exo) have been demonstrated to reduce vascular dysfunction, which may beneficially impact perivascular glymphatic clearance, and potentially, protein aggregates and the corresponding microstructural disruption. Methods We investigated the effect of CEC-Exo therapy on AD by assessing glymphatic transport, CSF motion, and microstructural integrity using magnetic resonance imaging (MRI), and measuring cognitive performance. TgF344-AD rats, at 12-months of age, were randomly treated with CEC-Exo (1×1011 particles/intravenous injection) or saline twice-weekly for four consecutive weeks. MRI measurements, including dynamic 3D T1-weighted imaging with contrast agent and diffusion MRI (dMRI) with multiple b-values, were conducted for all rats at 13-months. Glymphatic function was evaluated with tracer-induced time signal curve (TSC), while microstructural state and CSF motion were assessed with parameters derived from dMRI acquired at high (dMRIhigh-b) and low (dMRIlow-b) b-values, respectively. Cognitive performance was assessed by the Morris water maze (MWM) test. Results TSCs demonstrated significantly higher peak values in the olfactory bulb and whole brain in the CEC-Exo-treated group than in the saline-treated group. With the CEC-Exo treatment, a significantly increased MDlow-b, a measure of pseudorandom CSF motion derived from dMRIlow-b, was observed in the representative CSF-filled space. As revealed by dMRIhigh-b-derived parameters, CEC-Exo treatment resulted in significantly elevated axonal water fraction, fractional anisotropy, and Kurtosis in white matter, as well as significantly reduced mean diffusivity, axial diffusivity, and radial diffusivity in both white and gray matter in the AD brain. In the MWM test, CEC-Exo-treated rats spent a significantly greater percentage of time in the correct quadrant than did saline-treated rats. Conclusion CEC-Exo treatment preserved glymphatic transport, CSF motion, and microstructural integrity in the AD brain, accompanied by a reduced cognitive decline. With a global therapeutic impact, the CEC-Exo therapy provides a novel strategy on the treatment of AD. Our data support the value of dMRIlow-b as a clinically feasible imaging tool for assessing alterations in CSF dynamics that mediate perivascular glymphatic clearance.

Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.

Therapeutic Effects of miR-29b-Enriched Nanovesicles on Mitochondrial Injury and Neuroinflammatory Processes in Alzheimer’s Disease

Peripheral nerve-derived extracellular vesicles are dynamically regulated in chemotherapy-induced painful peripheral neuropathy