Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease

Abstract

SUMMARY Strong evidence implicates the complement pathway as an important contributor to amyloid pathology in Alzheimer’s disease (AD); however, the role of complement in tau modulation remains unclear. Here we show that the expression of C3 and C3a receptor (C3aR1) are positively correlated with cognitive decline and Braak staging in human AD brains. Deletion of C3ar1 in PS19 mice results in the rescue of tau pathology and attenuation of neuroinflammation, synaptic deficits, and neurodegeneration. Through RNA sequencing and cell type-specific transcriptomic analysis, we identify a C3aR-dependent transcription factor network that regulates a reactive glial switch whose inactivation ameliorates disease-associated microglia and neurotoxic astrocyte signatures. Strikingly, this C3aR network includes multiple genes linked to late-onset AD. Mechanistically we identify STAT3 as a direct target of C3-C3aR signaling that functionally mediates tau pathogenesis. All together our findings demonstrate a crucial role for activation of the C3-C3aR network in mediating neuroinflammation and tau pathology.

Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

“…While methodological differences such as hippocampal versus whole-brain effects may explain some of these differences, it is also interesting to note that Stat3 has Socs3-independent effects and vice versa (Panopoulos et al, 2006). In line with our results and attesting to the translational relevance, reduction in C3d receptor-mediated Stat3 signaling reduced neuroinflammation and pathology in a tau model of AD (Litvinchuk et al, 2018). Importantly, Stat3 deletion not only affected the classical hallmarks of AD pathology, but also had strong positive effects on cerebral network dysfunction, that is, a clinically highly relevant target in AD (Palop & Mucke, 2016;Reichenbach et al, 2018).…”

Questions and (some) answers on reactive astrocytes

“…In a complex in vivo multicellular environment with multiple stimuli, reactive astrocyte diversity may even be stronger. Both A1 and A2 genes are induced concomitantly in different models, such as mouse models of AD (Ceyzériat et al, ), Tauopathy (Litvinchuk et al, ), or ischemia (Liddelow et al, ).…”

“…Both A1 and A2 genes are induced concomitantly in different models, such as mouse models of AD (Ceyzériat et al, 2018), Tauopathy (Litvinchuk et al, 2018), or ischemia .…”

Modern approaches to investigating non‐neuronal aspects of Alzheimer's disease

“…Likewise, recent evidence has shown that tau P301S transgenic mice develop stereotypical tangles associated with AD in humans but only recapitulate the neurotoxicreactive astrocyte phenotype seen in patients following the forced expression of different human apolipoprotein E isoforms (13). In addition, it should be noted that PS19 t mice also appear to recapitulate up-regulation of A1 ADassociated reactive astrocyte transcripts and contain many C3 + GFAP + coimmunoreactive astrocytes (19).…”

“…Certain forms of reactive astrocytes have more defined markers of activation, such as signal transducer and activator of transcription 3 (STAT3) following acute spinal cord injury (11) or up-regulation of complement component C3 (C3) in neuroinflammatory-reactive astrocytes (12). More recent evidence, however, has shown strong colocalization of C3 and GFAP in tau P301S mice, pairing this apparent A1 neurotoxic-reactive phenotype with comprehensive quantitative PCR analyses of upregulated astrocyte-specific-reactive transcripts (19). In both of these instances, however, findings based on signals, such as STAT3 activation or C3 up-regulation may not be sufficiently definitive on their own and should be coupled with analysis of a broader range of reactive transcripts.…”