Dodel, R. C. et al. Intravenous immunoglobulins containing antibodies against β-amyloid for the treatment of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 75, 1472-1474

Philipps University of Marburg, Marburg, Hesse, Germany
Journal of Neurology Neurosurgery & Psychiatry (Impact Factor: 6.81). 11/2004; 75(10):1472-4. DOI: 10.1136/jnnp.2003.033399
Source: PubMed


Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer's disease (AD). Recently, it has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Abeta. This study reports the results from a pilot study using IVIgG in patients with AD.
Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Abeta/Abeta(1-42) measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG.
Following IVIgG, total Abeta levels in the CSF decreased by 30.1% (17.3-43.5%) compared to baseline (p<0.05). Total Abeta increased in the serum by 233% (p<0.05). No significant change was found in Abeta(1-42) levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7+/-2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline.
Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.

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    • "This effect may help explain the therapeutic benefits of intravenous immunoglobulins (IVIg), which have shown efficacy in slowing the progression of AD in some human clinical trials (Dodel et al., 2002; Dodel et al., 2004; Relkin et al., 2009; Loeffler, 2013). The benefits of IVIg are generally attributed to the presence of anti-Aβ antibodies in the pooled IgG preparations (Dodel et al., 2004). However, it is interesting to note that the administration of pooled mouse IgG having no detectable anti-Aβ activity to the brains of APP/ PS1 mice leads to a reduction in Aβ deposits similar to IVIg (Sudduth et al., 2013). "
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    ABSTRACT: Microglial cells in the brains of Alzheimer's patients are known to be recruited to amyloid-beta (Aβ) plaques where they exhibit an activated phenotype, but are defective for plaque removal by phagocytosis. In this study, we show that microglia stressed by exposure to sodium arsenite or Aβ(1–42) peptides or fibrils form extensive stress granules (SGs) to which the tyrosine kinase, SYK, is recruited. SYK enhances the formation of SGs, is active within the resulting SGs and stimulates the production of reactive oxygen and nitrogen species that are toxic to neuronal cells. This sequestration of SYK inhibits the ability of microglial cells to phagocytose Escherichia coli or Aβ fibrils. We find that aged microglial cells are more susceptible to the formation of SGs; and SGs containing SYK and phosphotyrosine are prevalent in the brains of patients with severe Alzheimer's disease. Phagocytic activity can be restored to stressed microglial cells by treatment with IgG, suggesting a mechanism to explain the therapeutic efficacy of intravenous IgG. These studies describe a mechanism by which stress, including exposure to Aβ, compromises the function of microglial cells in Alzheimer's disease and suggest approaches to restore activity to dysfunctional microglial cells.
    10/2015; DOI:10.1016/j.ebiom.2015.09.053
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    • "Natural autoantibodies against Aβ peptide and oligomers have been reported in the blood of healthy individuals and in IVIg preparations [8,9]. Initial evidence of IVIg efficacy comes from pilot studies in which IVIg improved cognition and reduced Aβ in the cerebrospinal fluid (CSF) in AD patients [10,11]. Results from a large phase III clinical trial ( "
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    ABSTRACT: Intravenous immunoglobulin (IVIg) is currently in clinical study for Alzheimer's disease (AD). However, preclinical investigations are required to better understand AD-relevant outcomes of IVIg treatment and develop replacement therapies in case of unsustainable supply. We investigated the effects of IVIg in the 3xTg-AD mouse model, which reproduces both Abeta and tau pathologies. Mice were injected twice weekly with 1.5 g/kg IVIg for 1 or 3 months. IVIg induced a modest but significant improvement in memory in the novel object recognition test and attenuated anxiety-like behavior in 3xTg-AD mice. We observed a correction of immunologic defects present in 3xTg-AD mice (-22% CD4/CD8 blood ratio; -17% IL-5/IL-10 ratio in the cortex) and a modulation of CX3CR1+ cell population (-13% in the bone marrow). IVIg treatment led to limited effects on tau pathology but resulted in a 22% reduction of the soluble Abeta42/Abeta40 ratio and a 60% decrease in concentrations of 56 kDa Abeta oligomers (Abeta*56). The memory-enhancing effect of IVIg reported here suggests that Abeta oligomers, effector T cells and the fractalkine pathway are potential pharmacological targets of IVIg in AD.
    Journal of Neuroinflammation 03/2014; 11(1):54. DOI:10.1186/1742-2094-11-54 · 5.41 Impact Factor
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    • "In addition, results from the studies conducted on Alzheimer's disease (AD) proved promising for the future (Dodel et al., 2004; Relkin et al., 2009). "
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    ABSTRACT: Stroke is one of the major reasons of death in the United States and related to adult disability. Despite aggressive research, the treatment approaches of stroke still remains a major clinical problem. Intravenous immunoglobulin (IVIg) is a polyspecific Ig G preparation obtained from plasma of several thousand healthy people (donors). IVIg is an important treatment approach and used for several disorders. The aim of this study was to investigate the potentially beneficial effects of IVIg therapy in experimentally induced ischemia in middle cerebral artery occlusion (MCAo) models of rats. A total of 30 adult male Sprague Dawley rats were used. The rats were divided into two equal groups, each consisting of 15 randomly selected rats: control group (n = 15) and IVIg group (n = 15). Intraluminal filament method was used for establishment of cerebral ischemia. Intraluminal filament was withdrawn after 2 h of MCAo and reperfusion started again and passed to therapeutic stages for all the groups. Physiologic saline solution of 0.5 ml/kg was administered to the control group and 400 mg/kg IVIg was given to the IVIg group rats intravenously. In neurological evaluation, the worst score was determined as 3 and the best score as 0. After routine process, the brain tissue was prepared histopathological investigation. The IVIg group showed significantly better recovery with respect to the control group by neurological examination. The observation of specimens obtained from IVIg groups showed that findings correlate with grade 1 and -2 histopathologically. Nevertheless, ischemic amendments were observed to comply with grade 3 in ischemic areas in control group. IVIg therapy can be used in the treatment of ischemic stroke patients.
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