Amyloid β plaque-associated proteins C1q and SAP enhance the Aβ1–42 peptide-induced cytokine secretion by adult human microglia in vitro
Abstract
Pro-inflammatory cytokines released by activated microglia could be a driving force in Alzheimer's disease (AD) pathology. We evaluated whether the presence of complement factor C1q and serum amyloid P component (SAP) in Abeta deposits is related to microglial activation. Activated microglia accumulate in SAP- and C1q-immunoreactive fibrillar amyloid beta (Abeta) plaques in AD temporal cortex. No clustered microglia are seen in SAP- and C1q-positive circumscript, non-fibrillar, tau-negative Abeta plaques in AD caudate nucleus and non-demented control temporal cortex. In addition, no clustered microglia were observed in C1q- and SAP-negative, irregular shaped, diffuse plaques in AD caudate nucleus and in non-demented control temporal cortex, which suggests that microglia are attracted and activated in Abeta deposits of certain fibrillarity that, in addition, have fixed SAP and C1q. Therefore, the effects of Abeta(1-42), SAP and C1q on cytokine secretion by human postmortem microglia in vitro were assessed. Abeta(1-42) alone had little to no effect. Abeta(1-42) peptides in combination with C1q or C1q and SAP increased microglial interleukin (IL)-6 secretion four- and eightfold, respectively. Tumor necrosis factor (TNF)-alpha, as well as intracellular IL-1alpha and IL-1beta levels, also increased upon exposure of microglia to Abeta(1-42)-SAP-C1q complexes. Combined with earlier findings, that amyloid and activated microglia accumulate at a relatively early stage of cognitive decline in AD patients, this suggests that clustering of activated, cytokine-secreting microglia in SAP- and C1q-containing Abeta deposits precedes neurodegenerative changes in AD, and thus may provide a "therapeutic window".
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Dysregulation of the complement system contributes to AD pathogenesis.
“Dysregulation of the complement system may also contribute to AD pathogenesis: C1q can enhance proinflammatory cytokines production induced by Aβ42 [372].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [372]
C1q enhances proinflammatory cytokine production induced by Aβ42.
“C1q can enhance proinflammatory cytokines production induced by Aβ42 [372].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [372]
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- Authors
- Veerhuis, R., Van Breemen, M. J., Hoozemans, J. J., Morbin, M., Ouladhadj, J., Tagliavini, F., & Eikelenboom, P.
- Affiliations
- Vrije Universiteit Amsterdam (NL)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Corresponding author
- Veerhuis, Robert
- Venue
- Acta Neuropathologica
- Published
- 2003-02
- Volume
- 105
- Issue
- 2
- Pages
- 135-144
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W504742713
- Cited by
- 123
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 7 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 3
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- Alzheimer's disease, amyloid plaques, C1q, serum amyloid P component, microglial activation, inflammatory cytokines, interleukin-6, TNF-α, interleukin-1, amyloid-beta 42, complement system, therapeutic window
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Serum Amyloid P-Component, Brain, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Microscopy, Electron, Middle Aged, Peptide Fragments, Complement C1q, Cytokines, Amyloid beta-Peptides, Microglia, Plaque, Amyloid, In Vitro Techniques
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