1. Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy.
- Author
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Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, Srinivasan K, Huntley MA, Wang Y, Wang TM, Hedehus M, Barck KH, Stark M, Ngu H, Foreman O, Meilandt WJ, Elstrott J, Chang MC, Hansen DV, Carano RAD, Sheng M, and Hanson JE
- Subjects
- Alzheimer Disease genetics, Animals, Atrophy, Behavior, Animal, Biomarkers metabolism, Brain pathology, Complement C1q metabolism, Complement C3 cerebrospinal fluid, Complement C3 genetics, Disease Models, Animal, Female, Gene Deletion, Gene Expression Regulation, Humans, Male, Mice, Transgenic, Nerve Degeneration genetics, Neurons metabolism, Neurons pathology, Plaque, Amyloid metabolism, Synapses metabolism, Alzheimer Disease immunology, Amyloidosis immunology, Complement C3 metabolism, Nerve Degeneration immunology, Tauopathies immunology
- Abstract
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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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