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

Neuron. 2018 Dec 19;100(6):1337-1353.e5. doi: 10.1016/j.neuron.2018.10.031. Epub 2018 Nov 8.


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.

Keywords: Alzheimer’s disease; C3aR; STAT3; complement; microglia; neuroinflammation; tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / complications
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Brain / pathology*
  • Brain / physiopathology
  • Calcium-Binding Proteins
  • Cognition Disorders / etiology
  • Complement C3a / genetics
  • Complement C3a / metabolism*
  • Cytokines / metabolism*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Evoked Potentials / physiology
  • Female
  • Gene Regulatory Networks / physiology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins
  • Middle Aged
  • Receptors, Complement / genetics
  • Receptors, Complement / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tauopathies / complications
  • Up-Regulation / physiology
  • tau Proteins / genetics
  • tau Proteins / metabolism


  • AIF1 protein, human
  • Calcium-Binding Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Microfilament Proteins
  • Receptors, Complement
  • complement C3a receptor
  • tau Proteins
  • Complement C3a