Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy
Open accessAbstract
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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Microglia and astrocytes coordinate their functions in many ways, both in the healthy and diseased brain.
“However, recent data indicate that microglia and astrocytes coordinate their functions in many ways, both in the healthy and diseased brain [14–21].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [21]
Previous transcriptomic studies comparing AD mouse models have reported similarities and differences in astrocyte responses to Aβ plaques versus pTau NFTs.
“Previous transcriptomic studies comparing AD mouse models have reported similarities and differences in astrocyte responses to Aβ plaques versus pTau NFTs5,7,33.”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [7]
SGK1 expression is increased in P301S Tau transgenic mice and in postmortem brain tissue from AD patients.
“RNA sequencing (RNAseq) of the prefrontal cortex (PFC) of the P301S human Tau transgenic mouse model of dementia has identified Serum and Glucocorticoid-regulated Kinase-1 (Sgk1) as one of the top-ranking upregulated genes [10].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [12]
The Induction of Brain Complement Expression section reports RNA-seq analysis of cells sorted from TauP301S mouse hippocampus and describes increased complement-gene expression, not Sgk1 expression in prefrontal cortex. The STAR+METHODS passages identify the RNA-seq datasets, but the passages retrieved for Sgk1 and prefrontal-cortex RNA-seq do not establish that Sgk1 was a top-ranking upregulated gene or that it increased in AD brain tissue. (LLM, conf=0.72)
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- Authors
- Wu, T., Dejanovic, B., Gandham, V. D., Gogineni, A., Edmonds, R., Schauer, S., Srinivasan, K., Huntley, M. A., Wang, Y., Wang, T.-M., Hedehus, M., Barck, K. H., Stark, M., Ngu, H., Foreman, O., Meilandt, W. J., Elstrott, J., Chang, M. C., Hansen, D. V., Carano, R. A. D., Sheng, M., & Hanson, J. E.
- Affiliations
- Genentech (US)
- Corresponding author
- Hanson, Jesse E.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 28
- Issue
- 8
- Pages
- 2111-2123.e6
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2969396388
- Cited by
- 466
- References
- 18
- Citations by year
- 2026: 61 · 2025: 71 · 2024: 65 · 2023: 77 · 2022: 74 · 2021: 77 · 2020: 36 · 2019: 4 · 2013: 1
- FWCI
- 32.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- complement C3, Alzheimer's disease, tauopathy, amyloidosis, neurodegeneration, complement overactivation, glial cells, synaptic loss, brain atrophy, tau protein, mouse model
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Atrophy, Behavior, Animal, Brain, Complement C3, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Male, Mice, Transgenic, Nerve Degeneration, Neurons, Synapses, Biomarkers, Complement C1q, Gene Deletion, Tauopathies, Plaque, Amyloid
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