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

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. •Pathological Tau accumulation alters protein composition of PSD in Tau-P301S mice•Loss of postsynaptic GTPase-regulatory proteins leads to loss of dendritic spines•C1q tags Tau-affected synapses, leading to microglial engulfment and synapse loss•C1q-blocking antibody prevents microglial synapse removal and rescues synapse density Unbiased proteomics reveals multiple molecular changes at hippocampal synapses that occur prior to neurodegeneration in a taupathy/Alzheimer’s disease mouse model. Complement C1q labels phospho-Tau-containing synapses and drives microglia-mediated synapse loss that can be rescued by a C1q-blocking antibody.