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Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease.
J Neuroinflammation. 2010 Dec 07; 7:90.JN

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 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 mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses.

METHODS

We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of Aβ burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD in vivo.

RESULTS

IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits ex vivo. IVIG enhanced microglia-mediated Aβ clearance ex vivo, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ 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 Aβ deposits in co-localization with microglia.

CONCLUSIONS

Our results demonstrate that IVIG promotes recognition and removal of natively formed brain Aβ deposits by primary microglia involving natural Aβ Abs in IVIG. These findings may have therapeutic relevance in vivo as IVIG penetrates through the blood-brain barrier and specifically binds to Aβ deposits in brain parenchyma.

Authors+Show Affiliations

Department of Neurobiology, A, I, Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. Johanna.Magga@uef.fiNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21138577

Citation

Magga, Johanna, et al. "Human Intravenous Immunoglobulin Provides Protection Against Aβ Toxicity By Multiple Mechanisms in a Mouse Model of Alzheimer's Disease." Journal of Neuroinflammation, vol. 7, 2010, p. 90.
Magga J, Puli L, Pihlaja R, et al. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease. J Neuroinflammation. 2010;7:90.
Magga, J., Puli, L., Pihlaja, R., Kanninen, K., Neulamaa, S., Malm, T., Härtig, W., Grosche, J., Goldsteins, G., Tanila, H., Koistinaho, J., & Koistinaho, M. (2010). Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease. Journal of Neuroinflammation, 7, 90. https://doi.org/10.1186/1742-2094-7-90
Magga J, et al. Human Intravenous Immunoglobulin Provides Protection Against Aβ Toxicity By Multiple Mechanisms in a Mouse Model of Alzheimer's Disease. J Neuroinflammation. 2010 Dec 7;7:90. PubMed PMID: 21138577.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease. AU - Magga,Johanna, AU - Puli,Lakshman, AU - Pihlaja,Rea, AU - Kanninen,Katja, AU - Neulamaa,Suvi, AU - Malm,Tarja, AU - Härtig,Wolfgang, AU - Grosche,Jens, AU - Goldsteins,Gundars, AU - Tanila,Heikki, AU - Koistinaho,Jari, AU - Koistinaho,Milla, Y1 - 2010/12/07/ PY - 2010/10/04/received PY - 2010/12/07/accepted PY - 2010/12/9/entrez PY - 2010/12/9/pubmed PY - 2011/4/13/medline SP - 90 EP - 90 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 7 N2 - 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 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 mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. METHODS: We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of Aβ burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD in vivo. RESULTS: IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits ex vivo. IVIG enhanced microglia-mediated Aβ clearance ex vivo, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ 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 Aβ deposits in co-localization with microglia. CONCLUSIONS: Our results demonstrate that IVIG promotes recognition and removal of natively formed brain Aβ deposits by primary microglia involving natural Aβ Abs in IVIG. These findings may have therapeutic relevance in vivo as IVIG penetrates through the blood-brain barrier and specifically binds to Aβ deposits in brain parenchyma. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/21138577/Human_intravenous_immunoglobulin_provides_protection_against_Aβ_toxicity_by_multiple_mechanisms_in_a_mouse_model_of_Alzheimer's_disease_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-7-90 DB - PRIME DP - Unbound Medicine ER -