RESUMO
Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan's syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.
Assuntos
Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de AMPA/metabolismo , Transmissão Sináptica/fisiologia , Idoso , Animais , Transtorno Autístico/genética , Autoanticorpos/imunologia , Autoantígenos/imunologia , Encefalite/imunologia , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Ratos , Ratos Wistar , Córtex Visual/metabolismoRESUMO
Herein, we investigate the bioactivity of small extracellular vesicles (sEVs), focusing on their local effect in the brain. sEVs from mononuclear cells (MNCs) showed superior effects in vitro to sEVs from mesenchymal stem cells (MSCs) and were able to promote neuroprotection and decrease microglia reactivity in a stroke mouse model.
Assuntos
Vesículas Extracelulares , Acidente Vascular Cerebral , Animais , Camundongos , Microglia , Neuroproteção , Encéfalo , Acidente Vascular Cerebral/terapia , Modelos Animais de DoençasRESUMO
No effective therapeutic dressings are currently available in the market that can prevent bacterial infection and simultaneously promote skin regeneration in diabetic patients. The lack of re-epithelization, prevalence of inflammation, and high risk of infection are hallmarks of non-healing wounds. Here, we have evaluated the antimicrobial and pro-regenerative effect of a relatively non-leaching LL37 peptide immobilized in polyurethane (PU)-based wound dressings (PU-adhesive-LL37 dressing). The PU-adhesive-LL37 (63 µg LL37NPs/cm2) dressing killed Gram-positive and Gram-negative bacteria in human serum without inducing bacterial resistance after 16 antimicrobial test cycles in contrast to commercially available dressings with the capacity to release antimicrobial Ag ions. Importantly, type II diabetic mice (db/db mice) treated with the PU-adhesive-LL37 dressing for different periods of time (6 or 14 days) showed enhanced wound healing and re-epithelialization (i.e., high keratin 14/5 levels) and lower macrophage infiltration in the wounds compared to animals treated with PU. The wounds treated with PU-adhesive-LL37 dressings showed also low expression of pro-inflammatory cytokines such as TNF-α and IL6 after 6 days of treatment, indicating that they act as an anti-inflammatory dressing. Additionally, PU-adhesive-LL37 dressings do not induce acute inflammatory responses in the peripheral blood mononuclear cells (PBMCs) after 3 days of exposure, in contrast to controls. Taken together, PU-adhesive-LL37NP dressings might prevent the bacterial infections and facilitate wound healing by tissue contact, inducing re-epithelialization and anti-inflammatory processes in diabetic conditions.
Assuntos
Infecções Bacterianas , Diabetes Mellitus Experimental , Animais , Antibacterianos/farmacologia , Peptídeos Antimicrobianos , Bandagens , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Humanos , Leucócitos Mononucleares , Camundongos , Poliuretanos/farmacologia , CicatrizaçãoRESUMO
Here we report a two-step surface modification methodology to radiolabel small extracellular vesicles (SEVs) with 64CuCl2 for PET/MRI imaging. The modification did not change or damage the morphology, surface receptor proteins and internal RNA content. Radiolabeled SEVs could be detected in organs with low accumulation such as the brain (0.4-0.5% ID g-1) and their brain location determined by MRI.