Plaque complement activation and cognitive loss in Alzheimer’s disease. J Neuroinflammation 5:9

Neurology Research Laboratory, William Beaumont Hospital Research Institute, Royal Oak, MI 48073, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 03/2008; 5(1):9. DOI: 10.1186/1742-2094-5-9
Source: PubMed


Complement activation is increased in Alzheimer's disease (AD), but its significance is unclear. The objective of this study was to determine the relationship between complement activation and cognition during the development of AD.
iC3b, C9, Bielschowsky, and Gallyas staining was performed on aged normal (n = 17), mild cognitively impaired (n = 12), and AD (n = 17-18) inferior temporal gyrus specimens. Plaques were counted in 10x fields with high numbers of Bielschowsky-stained plaques. One-way ANOVA was used to determine between-group differences for plaque counts and measures of cognitive function, and linear regression was used to evaluate global cognition as a function of Bielschowsky-stained plaques. Terms for iC3b- and C9-stained plaques were then added sequentially as additional predictors in a "mediation analysis" model.
Complement was detected on plaques in all groups, and on neurofibrillary tangles only in AD specimens. iC3b, C9, and Bielschowsky-stained plaque counts increased 2.5- to 3-fold in AD vs. other groups (all p < or = 0.01). C9 staining was present on some diffuse plaques, as well as on neuritic plaques. Bielschowsky-stained and complement-stained plaque counts were highly correlated, and were negatively correlated with cognitive measures. When the Bielschowsky plaque count was used as a predictor, its correlations with cognitive measures were statistically significant, but when iC3b and C9 plaque counts were added as additional predictors, these correlations were no longer significant. This loss of significance was attributed to multicollinearity, i.e., high correlations between Bielschowsky-stained and complement-stained plaque counts.
Both early-stage (iC3b) and late-stage (C9) complement activation occurs on neocortical plaques in subjects across the cognitive spectrum; contrary to previous reports, C9 is present on some diffuse plaques. Because of high correlations between complement-stained and Bielschowsky-stained plaque counts, quantitative assessment of the extent to which complement activation may mediate the relationship between plaques and cognitive function could not be performed. Additional studies with animal models of AD (if late-stage complement activation can be demonstrated), or possibly a trial in AD patients with an inhibitor of late-stage complement activation, may be necessary to determine the significance of this process in AD.

  • Source
    • "The significance of the complement activation in AD is not only the pathological changes in the terminal stage of AD but also reflects the early alternation in the disease course, i.e. mild cognitive impairment (MCI). For example, Loeffler et al. [58] have performed studies on iC3b, C9, Bielschowsky and Gallyas staining in in brains with 18 AD, 12 MCI with that from 17 aged normal controls and identified iC3b, C9, and Bielschowsky-stained plaque counts increased 2.5- to 3-fold in AD compared to MCI and control subjects. C9 staining was present on some diffuse plaques, as well as on neuritic plaques. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence suggests that inflammatory and immune components in brain are important in Alzheimer's disease (AD) and anti-inflammatory and immunotherapeutic approaches may be amenable to AD treatment. It is known that complement activation occurs in the brain of patients with AD, and contributes to a local inflammatory state development which is correlated with cognitive impairment. In addition to the complement's critical role in the innate immune system recognizing and killing, or targeting for destruction, complement proteins can also interact with cell surface receptors to promote a local inflammatory response and contributes to the protection and healing of the host. On the other hand, complement activation also causes inflammation and cell damage as an essential immune function to eliminate cell debris and potentially toxic protein aggregates. It is the balance of these seemingly competing events that influences the ultimate state of neuronal function. Our mini review will be focusing on the unique molecular interactions happening in the AD development, the functional outcomes of those interactions, as well as the contribution of each element to AD.
    Full-text · Article · Oct 2013 · Translational Neurodegeneration
  • Source
    • "At present, it is widely discussed that AMD shares common pathological hallmarks with Alzheimer's disease (AD) (Chiu et al. 2012; Dasari et al. 2011; Dentchev et al. 2003; Kaarniranta et al. 2011; Ohno- Matsui 2011; Yoshida et al. 2005). Like AD, AMD is characterized by Ab deposition and associated with changes in complement factors and ApoE (Laws et al. 2003; Loeffler et al. 2008). Oxidative stress and inflammation are strongly linked to pathogenesis of both diseases (Kaarniranta et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The main cause of vision loss in older individuals is age-related macular degeneration (AMD)-a complex multifactorial disease, whose etiology and pathogenesis are not completely understood. This is due to the impossibility of investigating the early stages of AMD and paucity of biological models. The senescence-accelerated OXYS rats develop retinopathy with clinical and morphological manifestations similar to AMD. But the genetic determinants of its development are not known. Previously we identified quantitative trait loci (QTLs) associated with the development of cataract, retinopathy, and behavioral signs in OXYS rat. In this study, we used bioinformatic analysis to show the enrichment of QTL region with genes associated with neurodegeneration, including a pathway of Alzheimer's disease. For selected list of candidate genes we designed oligonucleotide DNA chips. Using them we found small but significant changes in expression of several genes in OXYS retina compared to disease-free Wistar rats. Among the genes with altered expression were Picalm and Apba2, known to be participants in the processing of the beta-amyloid (Aβ). Measurement of Aβ 1-42 in the retina showed that its level increases with age in rats, and at advanced stages of retinopathy in OXYS rats, its expression becomes significantly higher than that of disease-free Wistar rats. Based on functional annotation of QTL, microarray, and ELISA results we suggest that accumulation of Aβ may have a role in the pathogenesis of retinopathy in OXYS rats.
    Full-text · Article · Aug 2013 · Biogerontology
  • Source
    • "Further cleavage of C3b results in smaller fragments designated iC3b, C3c and C3d, which may serve other unknown functions (Nishida et al., 2006). As with C1q, C3b and its cleavage product iC3b have been found deposited on AD-affected neurons (Loeffler et al., 2008), which would facilitate efficient removal by microglia. Although the activation of C1q in AD described above seems to have detrimental effects on CNS homeostasis, the story of C3 activation seems more complicated and may only function properly within specific ranges. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Of the many mysteries that surround the brain, few surpass the awe-inspiring complexity of its development. The intricate wiring of the brain at both the system and molecular level is both spatially and temporally regulated in perfect synchrony. How such a delicate, yet elegant, system arises from an embryo's most basic cells remains at the forefront of neuroscientific research. At the cellular level, the competitive dance between synapses struggling to gain dominance seems to be refereed by both neurons themselves and microglia, the innate immune cells of the nervous system. Additionally, the unexpected complement cascade, a major effecter arm of the innate immune system, is almost certainly involved in synaptic remodeling by tagging destined neurons and synapses for destruction. As suddenly as they appear, the mechanisms of neurogenesis recede entering into adulthood. However, with age and insult, these mechanisms boisterously return, resulting in neurodegeneration. This review describes some of the mechanisms involved in synaptogenesis and wiring of the brain from the point of view of the innate immune system and then covers how similar molecular processes return with age and disease, specifically in the context of Alzheimer's disease.
    Full-text · Article · Feb 2013 · Ageing research reviews
Show more