Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia.
acta neuropathol commun. 2019-05-22; 7(1):
DOI: 10.1186/s40478-019-0735-1
Lire sur PubMed
1. 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.
Hartmann K(1), Sepulveda-Falla D(1), Rose IVL(2)(3), Madore C(4), Muth C(1),
Matschke J(1), Butovsky O(4), Liddelow S(2)(3)(5), Glatzel M(1), Krasemann S(6).
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. .
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.
DOI: 10.1186/s40478-019-0735-1
PMCID: PMC6530067
PMID: 31118110 [Indexed for MEDLINE]