Format

Send to

Choose Destination
Acta Neuropathol Commun. 2019 May 22;7(1):83. doi: 10.1186/s40478-019-0735-1.

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

Author information

1
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
Neuroscience Institute; Neuroscience Institute, NYU Langone Medical Center, New York, USA.
3
Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, USA.
4
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
5
Department of Pharmacology and Therapeutics, the University of Melbourne, Melbourne, Australia.
6
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. s.krasemann@uke.de.

Abstract

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+-PrPSc-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 PrPSc 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+-PrPSc-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.

KEYWORDS:

A1-astrocytes; Microglia; Neurotoxicity; Prion diseases

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center