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Human intravenous immunoglobulin provides protection against A? toxicity by multiple mechanisms in a mouse model of Alzheimer's disease.

ABSTRACT: BACKGROUND: Purified intravenous immunoglobulin (IVIG) obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs) against ?-amyloid (A?) peptides accumulating in the brains of Alzheimer's disease (AD) patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain A? deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. METHODS: We first determined the effect of IVIG on A? toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of A? burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed A? deposits from brain sections of APP/PS1 mice or promotes A? removal by primary glial cells. We determined the role of lysosomal degradation pathway and A? Abs in the IVIG-promoted reduction of A?. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human A? in a mouse model of AD in vivo. RESULTS: IVIG was protective against A? toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic A?1-42 but did not solubilize natively formed brain A? deposits ex vivo. IVIG enhanced microglia-mediated A? clearance ex vivo, with a mechanism linked to A? Abs and lysosomal degradation. The IVIG-enhanced A? clearance appears specific for microglia since IVIG did not affect A? clearance by astrocytes. The cellular mechanisms of A? clearance we observed have potential relevance in vivo since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest concentrations in the hippocampus and bound selectively to A? deposits in co-localization with microglia. CONCLUSIONS: Our results demonstrate that IVIG promotes recognition and removal of natively formed brain A? deposits by primary microglia involving natural A? Abs in IVIG. These findings may have therapeutic relevance in vivo as IVIG penetrates through the blood-brain barrier and specifically binds to A? deposits in brain parenchyma.

SUBMITTER: Magga J

PROVIDER: S-EPMC3004875 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease.

Magga Johanna J Puli Lakshman L Pihlaja Rea R Kanninen Katja K Neulamaa Suvi S Malm Tarja T Härtig Wolfgang W Grosche Jens J Goldsteins Gundars G Tanila Heikki H Koistinaho Jari J Koistinaho Milla M

Journal of neuroinflammation 20101207

<h4>Background</h4>Purified intravenous immunoglobulin (IVIG) obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs) against β-amyloid (Aβ) peptides accumulating in the brains of Alzheimer's disease (AD) patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its ...[more]

PMID: 21138577

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Project description:Manganese biomineralization is a widespread process among bacteria and fungi. To date, there is no conclusive experimental evidence for how and if this process impacts microbial fitness in the environment. Here, we show how a model organism for manganese oxidation is growth inhibited by nitrite, and that this inhibition is mitigated in the presence of manganese. We show that such manganese-mediated mitigation of nitrite inhibition is dependent on the culture inoculum size, and that manganese oxide (MnOX) forms granular precipitates in the culture, rather than sheaths around individual cells. We provide evidence that MnOX protection involves both its ability to catalyze nitrite oxidation into (nontoxic) nitrate under physiological conditions and its potential role in influencing processes involving reactive oxygen species (ROS). Taken together, these results demonstrate improved microbial fitness through MnOX deposition in an ecological setting, i.e., mitigation of nitrite toxicity, and point to a key role of MnOX in handling stresses arising from ROS.IMPORTANCE We present here a direct fitness benefit (i.e., growth advantage) for manganese oxide biomineralization activity in Roseobacter sp. strain AzwK-3b, a model organism used to study this process. We find that strain AzwK-3b in a laboratory culture experiment is growth inhibited by nitrite in manganese-free cultures, while the inhibition is considerably relieved by manganese supplementation and manganese oxide (MnOX) formation. We show that biogenic MnOX interacts directly with nitrite and possibly with reactive oxygen species and find that its beneficial effects are established through formation of dispersed MnOX granules in a manner dependent on the population size. These experiments raise the possibility that manganese biomineralization could confer protection against nitrite toxicity to a population of cells. They open up new avenues of interrogating this process in other species and provide possible routes to their biotechnological applications, including in metal recovery, biomaterials production, and synthetic community engineering.

Dataset Information

Human intravenous immunoglobulin provides protection against A? toxicity by multiple mechanisms in a mouse model of Alzheimer's disease.

Publications

Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease.

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