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

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

doi:10.1186/s40478-019-0735-1

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.

Highlights

Prion diseases are neurodegenerative disorders that are always fatal and affect humans and animals alike
A1 astrocytes are highly abundant in mouse and human prion diseases Reactive astrogliosis is a hallmark of human neurodegenerative diseases, it is highly abundant in prion disease mouse models and human prion diseases [41, 45]
If formation of A1-astrocytes plays a role in human prion diseases, we stained human brain tissue sections for the putative A1-astrocyte markers complement 3 (C3) (Additional file 1: Figure S1b) and guanine-binding protein 2 (GBP2) (Fig. 1b, c, Additional file 1: Figure S1b) [39]

Summary

Introduction

Prion diseases are neurodegenerative disorders that are always fatal and affect humans and animals alike. Sporadic Creutzfeldt–Jakob disease (sCJD) is the most common human prion disorder. Microglia are highly activated in prion disease mouse models and human prion diseases [34, 36]. Recent investigations have shown that microglia cells act beneficially at least in the early phases in in vitroand mouse models of prion diseases [12, 49, 65]. While microglia seem to be able to clear PrPSc at early disease stages, it was shown that microglia lose their PrPSc degrading function during disease progression [28]. Microglia are the professional phagocytes of the brain, they get pro-inflammatory in the course of neurodegenerative diseases and may thereby contribute to neuronal loss in the late disease stages [1, 33]

Methods

Results

Discussion

Conclusion