Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

Neuron. 2018 Dec 19;100(6):1322-1336.e7. doi: 10.1016/j.neuron.2018.10.014. Epub 2018 Nov 1.

Abstract

Synapse loss and Tau pathology are hallmarks of Alzheimer's disease (AD) and other tauopathies, but how Tau pathology causes synapse loss is unclear. We used unbiased proteomic analysis of postsynaptic densities (PSDs) in Tau-P301S transgenic mice to identify Tau-dependent alterations in synapses prior to overt neurodegeneration. Multiple proteins and pathways were altered in Tau-P301S PSDs, including depletion of a set of GTPase-regulatory proteins that leads to actin cytoskeletal defects and loss of dendritic spines. Furthermore, we found striking accumulation of complement C1q in the PSDs of Tau-P301S mice and AD patients. At synapses, C1q decorated perisynaptic membranes, accumulated in correlation with phospho-Tau, and was associated with augmented microglial engulfment of synapses and decline of synapse density. A C1q-blocking antibody inhibited microglial synapse removal in cultured neurons and in Tau-P301S mice, rescuing synapse density. Thus, inhibiting complement-mediated synapse removal by microglia could be a potential therapeutic target for Tau-associated neurodegeneration.

Keywords: Alzheimer’s disease; C1q; GTPase; Tau; complement; mass spectrometry; neurodegeneration; postsynaptic density; proteomics; synapse.

MeSH terms

  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Animals, Newborn
  • Antibodies / therapeutic use*
  • Cell Differentiation
  • Cells, Cultured
  • Complement C1q / immunology*
  • Complement C1q / metabolism
  • Complement C1q / ultrastructure
  • Embryo, Mammalian
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Post-Synaptic Density / metabolism
  • Post-Synaptic Density / pathology
  • Post-Synaptic Density / ultrastructure
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism
  • Prion Proteins / genetics
  • Prion Proteins / metabolism
  • Proteome / metabolism
  • Rats
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Tauopathies / diagnostic imaging
  • Tauopathies / drug therapy*
  • Tauopathies / genetics
  • Tauopathies / pathology*
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Antibodies
  • PRNP protein, human
  • Presenilin-2
  • Prion Proteins
  • Proteome
  • tau Proteins
  • Complement C1q