Mechanisms of Synapse Loss Revealed by Proteomic Analysis of Post-Synaptic Density in Tauopathy Mouse Model

Identification: Sheng, Morgan

Mechanisms of Synapse Loss Revealed by Proteomic Analysis of Postsynaptic Density in Tauopathy Mouse Model
Morgan Sheng
Genentech, Inc., South San Francisco, CA, USA
Synaptic dysfunction and synapse loss are hallmarks of Alzheimer's disease (AD) and other tauopathies, yet the underlying molecular pathomechanism remains largely undefined. Here, we used unbiased proteomic analysis of postsynaptic density (PSD) proteins from wild-type versus Tau-P301S transgenic mice before the onset of overt neurodegeneration to identify early tau-dependent changes in the synapse. We identified that C1q, initiator of the classical complement cascade, is highly increased in PSDs purified from Tau-P301S hippocampus, and that C1q is present at synapses. Tau-P301S brains had increased engulfment of synaptic material by microglia. Moreover, C1q-neutralizing antibodies suppressed microglial synapse clearance in neuron-microglia co-cultures and in vivo in Tau-P301S mice. These findings suggest that tau pathology induces tagging of synapses by C1q, leading to removal of synapses by microglia, and raise the possibility that C1q-neutralizing antibodies might be a potential approach to mitigate synapse loss in AD.


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