Idioma:

Complement 3 + -astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia

Hartmann, Kristin ; Sepulveda-Falla, Diego ; Rose, Indigo V L ; Madore, Charlotte ; Muth, Christiane ; Matschke, Jakob ; Butovsky, Oleg ; Liddelow, Shane ; Glatzel, Markus ; Krasemann, Susanne

Acta neuropathologica communications, 2019-05, Vol.7 (1), p.83-15, Article 83 [Periódico revisado por pares]

England: BioMed Central Ltd

Texto completo disponível

Citações Citado por

Enviar para

Título:
Complement 3 + -astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia
Autor: Hartmann, Kristin ; Sepulveda-Falla, Diego ; Rose, Indigo V L ; Madore, Charlotte ; Muth, Christiane ; Matschke, Jakob ; Butovsky, Oleg ; Liddelow, Shane ; Glatzel, Markus ; Krasemann, Susanne
Assuntos: A1-astrocytes ; Aged ; Animals ; Antibodies ; Astrocytes ; Astrocytes - metabolism ; Astrocytes - pathology ; Brain ; Carprofen ; Complement C3 - metabolism ; Creutzfeldt-Jakob Syndrome - metabolism ; Creutzfeldt-Jakob Syndrome - pathology ; Cytokines ; Cytokines - genetics ; Cytokines - metabolism ; Development and progression ; Disease ; Disease Progression ; Ethics ; Female ; Health aspects ; Humans ; Immunoglobulins ; Investigations ; Laboratory animals ; Life Sciences ; Male ; Medical research ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia ; Microglia - metabolism ; Microglia - pathology ; Middle Aged ; Nervous system diseases ; Neurodegeneration ; Neurodegenerative diseases ; Neurotoxicity ; Neurotoxicity syndromes ; Prion diseases ; Prion Diseases - metabolism ; Prion Diseases - pathology ; Proteins ; PrPSc Proteins - metabolism ; Risk factors ; Rodents ; Tumor necrosis factor
É parte de: Acta neuropathologica communications, 2019-05, Vol.7 (1), p.83-15, Article 83
Notas: PMCID: PMC6530067
Descrição: Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinflammatory microglial cytokine cocktail containing TNF-α, IL-1α and C1qa reprograms a subset of astrocytes to change their expression profile and phenotype, thus becoming neurotoxic (designated as A1-astrocytes). Knockout or antibody blockage of the three cytokines abolish formation of A1-astrocytes, therefore, this pathway is of high therapeutic interest in neurodegenerative diseases. Since astrocyte polarization profiles have never been investigated in prion diseases, we performed several analyses and could show that C3 -PrP -reactive-astrocytes, which may represent a subtype of A1-astrocytes, are highly abundant in prion disease mouse models and human prion diseases. To investigate their impact on prion disease pathophysiology and to evaluate their potential therapeutic targeting, we infected TNF-α, IL-1α, and C1qa Triple-KO mice (TKO-mice), which do not transit astrocytes into A1, with prions. Although formation of C3 -astrocytes was significantly reduced in prion infected Triple-KO-mice, this did not affect the amount of PrP deposition or titers of infectious prions. Detailed characterization of the astrocyte activation signature in thalamus tissue showed that astrocytes in prion diseases are highly activated, showing a mixed phenotype that is distinct from other neurodegenerative diseases and were therefore termed C3 -PrP -reactive-astrocytes. Unexpectedly, Triple-KO led to a significant acceleration of prion disease course. While pan-astrocyte and -microglia marker upregulation was unchanged compared to WT-brains, microglial homeostatic markers were lost early in disease in TKO-mice, pointing towards important functions of different glia cell types in prion diseases.
Editor: England: BioMed Central Ltd
Idioma: Inglês

Links

Voltar para lista de resultados

Realização: Logos de Redes Sociais:

Complement 3 + -astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia

Hartmann, Kristin ; Sepulveda-Falla, Diego ; Rose, Indigo V L ; Madore, Charlotte ; Muth, Christiane ; Matschke, Jakob ; Butovsky, Oleg ; Liddelow, Shane ; Glatzel, Markus ; Krasemann, Susanne

England: BioMed Central Ltd

Buscando em bases de dados remotas. Favor aguardar.