RESUMO
The severity of tau pathology in Alzheimer's disease brain correlates closely with disease progression. Tau immunotherapy has therefore been proposed as a new therapeutic approach to Alzheimer's disease and encouraging results have been obtained by active or passive immunization of tau transgenic mice. This work investigates the mechanism by which immunotherapy can impact tau pathology. We demonstrate the development of Alzheimer's disease-like tau pathology in a triple transgenic mouse model of Alzheimer's disease and show that tau/pS422 is present in membrane microdomains on the neuronal cell surface. Chronic, peripheral administration of anti-tau/pS422 antibody reduces the accumulation of tau pathology. The unequivocal presence of anti-tau/pS422 antibody inside neurons and in lysosomes is demonstrated. We propose that anti-tau/pS422 antibody binds to membrane-associated tau/pS422 and that the antigen-antibody complexes are cleared intracellularly, thereby offering one explanation for how tau immunotherapy can ameliorate neuronal tau pathology.
Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Anticorpos/metabolismo , Proteínas tau/imunologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Western Blotting , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Progressão da Doença , Imunofluorescência , Humanos , Processamento de Imagem Assistida por Computador , Lisossomos/metabolismo , Lisossomos/patologia , Microdomínios da Membrana/patologia , Camundongos , Camundongos Transgênicos , Fosforilação , Sarcosina/análogos & derivados , Sarcosina/químicaRESUMO
Background: In some people with Parkinson's disease (PD), α-synuclein (αSyn) accumulation may begin in the enteric nervous system (ENS) decades before development of brain pathology and disease diagnosis. Objective: To determine how different types and severity of intestinal inflammation could trigger αSyn accumulation in the ENS and the subsequent development of αSyn brain pathology. Methods: We assessed the effects of modulating short- and long-term experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice by immunostaining and gene expression analysis. To determine the long-term effect on the brain, we induced dextran sulfate sodium (DSS) colitis in young αSyn transgenic mice and aged them under normal conditions up to 9 or 21 months before tissue analyses. Results: A single strong or sustained mild DSS colitis triggered αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS colitis or inflammation induced by lipopolysaccharide did not have such an effect. Genetic and pharmacological modulation of macrophage-associated pathways modulated the severity of enteric αSyn. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons. Conclusions: Our data suggest that specific types and severity of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.