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Cited by 213Complement system in diseasesAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Complement in the pathogenesis of Alzheimer’s disease

Open access
Morgan, B. Paul·2018·Seminars in Immunopathology
DOI 10.1007/s00281-017-0662-9PMC PMC5794825
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Abstract

The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimer's disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimer's disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain.

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Figures

Fig. 1 Complement dysregulation in the AD brain. Complement (C) may access the brain parenchyma from plasma through a disrupted BBB or may be made locally by glia and/or neurones. Complement is activated (via the CP) on amyloid plaques; this may facilitate opsonic clearance but also drives inflammatory activation of glia via C5a (and C3a). Activated microglia synthesise inflammatory cytokines and more complement proteins, stokeing the flames. Complement activation on neurones and oligodendrocytes leads directly to cell damage and death. Injured and dead cells activate more complement, leading to dysregulation, further inflammation and tissue damage
Fig. 1 Complement dysregulation in the AD brain. Complement (C) may access the brain parenchyma from plasma through a disrupted BBB or may be made locally by glia and/or neurones. Complement is activated (via the CP) on amyloid plaques; this may facilitate opsonic clearance but also drives inflammatory activation of glia via C5a (and C3a). Activated microglia synthesise inflammatory cytokines and more complement proteins, stokeing the flames. Complement activation on neurones and oligodendrocytes leads directly to cell damage and death. Injured and dead cells activate more complement, leading to dysregulation, further inflammation and tissue damageCC BY · PubMed Central
Fig. 2 Complement components and activation products in the AD brain. Examples of AD brain sections stained with different complement antibodies: plaques stain strongly for C1q, MAC and CFH. Neurones are also strongly positive for CFH. Aβ40 staining of plaques is shown as a control
Fig. 2 Complement components and activation products in the AD brain. Examples of AD brain sections stained with different complement antibodies: plaques stain strongly for C1q, MAC and CFH. Neurones are also strongly positive for CFH. Aβ40 staining of plaques is shown as a controlCC BY · PubMed Central
Fig. 3 Association of SNPs in CR1 and CFH with AD. a The short (CR1*1) and long (CR1*2) variants of CR1 are illustrated, differing by the acquisition of an extra LHR (LHR-S) in the long forms; CR1*2 is strongly associated with the risk allele at the rs6656401 SNP. Individual SCRs are represented by ovals. Binding sites for C3b, C4b and CR1 are indicated. The T1610S (rs4844609) coding SNP in the 26th SCR is adjacent the C1q binding site in LHR-D. b CFH comprises a string of 20 SCRs. Binding sites for C3b, C3d and glycosaminoglycans (GAGs) are indicated. The two coding SNPs associated with AD in some ethnic groups respectively cause single amino acid changes I62V (at the interface of SCRs 1 and 2 and in the C3b binding site) and Y402H (in SCR 7 and part of a GAG binding site)
Fig. 3 Association of SNPs in CR1 and CFH with AD. a The short (CR1*1) and long (CR1*2) variants of CR1 are illustrated, differing by the acquisition of an extra LHR (LHR-S) in the long forms; CR1*2 is strongly associated with the risk allele at the rs6656401 SNP. Individual SCRs are represented by ovals. Binding sites for C3b, C4b and CR1 are indicated. The T1610S (rs4844609) coding SNP in the 26th SCR is adjacent the C1q binding site in LHR-D. b CFH comprises a string of 20 SCRs. Binding sites for C3b, C3d and glycosaminoglycans (GAGs) are indicated. The two coding SNPs associated with AD in some ethnic groups respectively cause single amino acid changes I62V (at the interface of SCRs 1 and 2 and in the C3b binding site) and Y402H (in SCR 7 and part of a GAG binding site)CC BY · PubMed Central
Fig. 4 Plasma complement biomarkers predict progression in mild cognitive impairment (MCI). Results of a multivariate analysis to identify the best plasma complement biomarkers to differentiate AD from controls (a) and to predict progression in individuals with MCI (b). Only clusterin was significant in the first analysis; with ApoE status, it gave a predictive power (AUC) of 0.78. Clusterin, CFI and TCC were together highly predictive of progression in MCI (AUC of 0.85). Modified from Reference [81]
Fig. 4 Plasma complement biomarkers predict progression in mild cognitive impairment (MCI). Results of a multivariate analysis to identify the best plasma complement biomarkers to differentiate AD from controls (a) and to predict progression in individuals with MCI (b). Only clusterin was significant in the first analysis; with ApoE status, it gave a predictive power (AUC) of 0.78. Clusterin, CFI and TCC were together highly predictive of progression in MCI (AUC of 0.85). Modified from Reference [81]CC BY · PubMed Central
Fig. 5 Getting anti-complement drugs into the AD brain. Carrier-mediated transport (CMT) actively delivers some small-molecule drugs into the brain (1), utilising one of a large number of intracellular transporters. A small-molecule anti-complement drug (illustrated in red) could be designed to engage CMT for delivery across the BBB. For larger molecules, ‘Trojan Horse’ methods can be utilised to deliver, hijacking receptor-mediated transport (RMT) systems. Chimeric antibodies capable of binding a relevant receptor (usually either the transferrin receptor or the insulin receptor) through one arm and carrying an anti-complement site on the other (in red; anti-C1q; anti-C5 etc) will be transported across the BBB and released into the brain parenchyma to inhibit complement. Alternatively, a complement regulator can be coupled recombinantly or chemically to the anti-receptor antibody (3), allowing it to piggy-back across the BBB
Fig. 5 Getting anti-complement drugs into the AD brain. Carrier-mediated transport (CMT) actively delivers some small-molecule drugs into the brain (1), utilising one of a large number of intracellular transporters. A small-molecule anti-complement drug (illustrated in red) could be designed to engage CMT for delivery across the BBB. For larger molecules, ‘Trojan Horse’ methods can be utilised to deliver, hijacking receptor-mediated transport (RMT) systems. Chimeric antibodies capable of binding a relevant receptor (usually either the transferrin receptor or the insulin receptor) through one arm and carrying an anti-complement site on the other (in red; anti-C1q; anti-C5 etc) will be transported across the BBB and released into the brain parenchyma to inhibit complement. Alternatively, a complement regulator can be coupled recombinantly or chemically to the anti-receptor antibody (3), allowing it to piggy-back across the BBBCC BY · PubMed Central

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Metadata

Authors
Morgan, B. P.
Affiliations
Cardiff University (GB)
Corresponding author
Morgan, B. Paul
ORCID
Morgan, B. Paul
Venue
Seminars in Immunopathology
Publisher
Springer Science and Business Media LLC
Published
2017-11-13
Volume
40
Issue
1
Pages
113-124
ISSN
  • 1863-2297 (ISSN-L)
  • 1863-2300
DOI
10.1007/s00281-017-0662-9
PMC
PMC5794825
OpenAlex
W2769984699
Cited by
194
References
93
Citations by year
2026: 14 · 2025: 16 · 2024: 35 · 2023: 16 · 2022: 18 · 2021: 32 · 2020: 31 · 2019: 22 · 2018: 10
FWCI
1.77
Type
journal article
Language
en
Update notices
correction (2018-09-21)
Open access
Licence
Locations
  • Seminars in Immunopathology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
Funders
Cardiff University
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
complement system, Alzheimer's disease, complement inhibition therapy, neuroinflammation, brain homeostasis, dementia pathogenesis

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