RESUMEN
The composition of the intestinal microbiome affects health from the prenatal period throughout childhood, and many diseases have been associated with dysbiosis. The gut microbiome is constantly changing, from birth throughout adulthood, and several variables affect its development and content. Features of the intestinal microbiota can affect development of the brain, immune system, and lungs, as well as body growth. We review the development of the gut microbiome, proponents of dysbiosis, and interactions of the microbiota with other organs. The gut microbiome should be thought of as an organ system that has important effects on childhood development. Dysbiosis has been associated with diseases in children and adults, including autism, attention deficit hyperactivity disorder, asthma, and allergies.
Asunto(s)
Desarrollo Infantil/fisiología , Disbiosis/fisiopatología , Microbioma Gastrointestinal/fisiología , Adolescente , Peso Corporal/fisiología , Sistema Nervioso Central/crecimiento & desarrollo , Niño , Preescolar , Disbiosis/microbiología , Ambiente , Femenino , Salud , Estado de Salud , Humanos , Sistema Inmunológico/crecimiento & desarrollo , Sistema Inmunológico/fisiopatología , Lactante , Recién Nacido , Pulmón/crecimiento & desarrollo , Pulmón/fisiología , Pulmón/fisiopatologíaRESUMEN
Anti-Abeta antibody administration to amyloid-depositing transgenic mice can reverse amyloid pathology and restore memory function. However, in old mice, these treatments also increase vascular leakage and promote formation of vascular amyloid deposits. Deglycosylated antibodies with reduced affinity for Fcgamma receptors and complement are associated with reduced vascular amyloid and microhemorrhage while retaining amyloid-clearing and memory-enhancing properties of native intact antibodies. In the current experiment, we investigated the effect of 3, 10, or 30 mg/kg of deglycosylated antibody (D-2H6) on amyloid pathology and cognitive behavior in old Tg2576 mice. We found that low doses of deglycosylated antibody appear more efficacious than higher doses in reducing pathology and memory loss in amyloid precursor protein (APP) transgenic mice. These data suggest that excess antibody unbound to antigen can interfere with antibody-mediated Abeta clearance, possibly by saturating the FcRn antibody transporter.
Asunto(s)
Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Anticuerpos/administración & dosificación , Anticuerpos/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Memoria/fisiología , Envejecimiento/genética , Amiloide/antagonistas & inhibidores , Amiloide/metabolismo , Animales , Relación Dosis-Respuesta Inmunológica , Glicosilación , Ratones , Ratones TransgénicosRESUMEN
Abeta-induced neurodegeneration is limited in APP and APP+PS1 transgenic mice. In middle-aged APP + PS1 transgenic mice, we found significantly increased Bcl-2 expression. The increase in Bcl-2 is restricted to amyloid-containing brain regions and is not found at young ages, suggesting that Abeta deposition is the stimulus for increased Bcl-2. Western blot results were confirmed with immunohistochemistry and qRT-PCR. In addition, we found that APP transgenic mice were protected from neurotoxicity caused by an injection of bak BH3 fusion peptides, known to induce apoptosis by antagonizing bcl protein activity. Nissl and fluorojade-stained slides showed that the active bak BH3 peptide caused substantial neuronal loss in the dentate gyrus and CA3 regions of nontransgenic, but not APP mice. The inactive mutant bak BH3 peptide did not cause degeneration in any mice. These data demonstrate that the increased Bcl-2 expression in brain regions containing Abeta deposits is associated with neuroprotection.
Asunto(s)
Péptidos beta-Amiloides/genética , Amiloidosis/genética , Amiloidosis/patología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Animales , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/farmacología , Western Blotting , Muerte Celular/genética , Muerte Celular/fisiología , Cerebelo/metabolismo , Cerebelo/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Ratones , Ratones Transgénicos , Neuronas/patología , Presenilina-1/biosíntesis , Presenilina-1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tálamo/metabolismo , Tálamo/patología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Systemic administration of anti-amyloid-beta (Abeta) antibodies results in reduced parenchymal amyloid but increased vascular amyloid and microhemorrhage in amyloid precursor protein (APP) transgenic mice. Here, we evaluate the effects of reducing effector interactions of the antibody via deglycosylation. Mice aged 20 months were treated weekly for 4 months and tested behaviorally before they were killed. APP transgenic mice receiving either anti-Abeta (2H6) or deglycosylated anti-Abeta (de-2H6) showed significant improvement in radial arm water maze performance compared with mice receiving a control antibody. Both groups receiving anti-Abeta antibodies showed significant reductions in total Abeta immunochemistry and Congo red. Significantly fewer vascular amyloid deposits and microhemorrhages were observed in mice administered the de-2H6 antibody compared with those receiving unmodified 2H6 antibody. Deglycosylated anti-Abeta antibodies may be preferable to unmodified IgG because they retain the cognition-enhancing and amyloid-reducing properties of anti-Abeta immunotherapy, while greatly attenuating the increased vascular amyloid deposition and microhemorrhage observed with unmodified IgG.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/metabolismo , Anticuerpos/farmacología , Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Placa Amiloide/efectos de los fármacos , Envejecimiento/metabolismo , Envejecimiento/patología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Anticuerpos/uso terapéutico , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Enfermedades Arteriales Cerebrales/tratamiento farmacológico , Enfermedades Arteriales Cerebrales/fisiopatología , Enfermedades Arteriales Cerebrales/prevención & control , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/prevención & control , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Glicosilación , Inmunoterapia/métodos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Transgénicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Antibodies against the Ass peptide clear Ass deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation. METHODS: Deglycosylated or intact C-terminal specific high affinity anti-Abeta antibody (2H6) were intracranially injected into the right frontal cortex and hippocampus of amyloid precursor protein (APP) transgenic mice. The untreated left hemisphere was used to normalize for the extent of amyloid deposition present in each mouse. Control transgenic mice were injected with an antibody against a drosophila-specific protein (amnesiac). Tissues were examined for brain amyloid deposition and microglial responses 3 days after the injection. RESULTS: The deglycosylated 2H6 antibody had lower affinity for several murine Fcgamma receptors and human complement than intact 2H6 without a change in affinity for Ass. Immunohistochemistry for Abeta and thioflavine-S staining revealed that both diffuse and compact deposits were reduced by both antibodies. In animals treated with the intact 2H6 antibody, a significant increase in Fcgamma-receptor II/III immunostaining was observed compared to animals treated with the control IgG antibody. No increase in Fcgamma-receptor II/III was found with the deglycosylated 2H6 antibody. Immunostaining for the microglial activation marker CD45 demonstrated a similar trend. CONCLUSION: These findings suggest that the deglycosylated 2H6 is capable of removing both compact and diffuse plaques without activating microglia. Thus, antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease.