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Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy. 2019
Tiffany Wu, and
Borislav Dejanovic, and
Vineela D Gandham, and
Alvin Gogineni, and
Rose Edmonds, and
Stephen Schauer, and
Karpagam Srinivasan, and
Melanie A Huntley, and
Yuanyuan Wang, and
Tzu-Ming Wang, and
Maj Hedehus, and
Kai H Barck, and
Maya Stark, and
Hai Ngu, and
Oded Foreman, and
William J Meilandt, and
Justin Elstrott, and
Michael C Chang, and
David V Hansen, and
Richard A D Carano, and
Morgan Sheng, and
Jesse E Hanson
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by β-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.
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