RESUMO
BACKGROUND: The purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo. METHODS: We employed the inducible Col1-IL1ßXAT mouse model of osteoarthritis, in which induction of osteoarthritis in the knees and temporomandibular joints resulted in astrocyte and microglial activation in the brain, accompanied by upregulation of inflammation-related gene expression. The biological significance of the link between peripheral and brain inflammation was explored in the APP/PS1 mouse model of Alzheimer's disease (AD) whereby osteoarthritis resulted in neuroinflammation as well as exacerbation and acceleration of AD pathology. RESULTS: Induction of osteoarthritis exacerbated and accelerated the development of neuroinflammation, as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aß pathology, assessed by the number and size of amyloid plaques, in the APP/PS1; Col1-IL1ßXAT compound transgenic mouse. CONCLUSION: This work supports a model by which peripheral inflammation triggers the development of neuroinflammation and subsequently the induction of AD pathology. Better understanding of the link between peripheral localized inflammation, whether in the form of osteoarthritis, atherosclerosis or other conditions, and brain inflammation, may prove critical to our understanding of the pathophysiology of disorders such as Alzheimer's, Parkinson's and other neurodegenerative diseases.
Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Inflamação/complicações , Inflamação/imunologia , Osteoartrite/complicações , Osteoartrite/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/fisiologia , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Colágeno Tipo I/genética , Colágeno Tipo I/imunologia , Modelos Animais de Doenças , Humanos , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoartrite/fisiopatologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologiaRESUMO
Myeloid-derived immune cells, including microglia, macrophages and monocytes, have been previously implicated in neurodegeneration. We investigated the role of infiltrating peripheral blood mononuclear cells (PBMC) in neuroinflammation and neurodegeneration in the HexB-/- mouse model of Sandhoff disease. Ablation of the chemokine receptor CCR2 in the HexB-/- mouse resulted in significant inhibition of PBMC infiltration into the brain, decrease in TNFalpha and MHC-II mRNA abundance and retardation in clinical disease development. There was no change in the level of GM2 storage and pro-apoptotic activity or astrocyte activation in HexB-/-; Ccr2-/- double knockout mice, which eventually succumbed secondary to GM2 gangliosidosis.
