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

Magga Johanna, Puli Lakshman, Pihlaja Rea, Kanninen Katja, Neulamaa Suvi, Malm Tarja, Härtig Wolfgang, Grosche Jens, Goldsteins Gundars, Tanila Heikki, Koistinaho Jari, Koistinaho Milla

Description

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.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2010
• Nombre de lectures: 4
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Maggaet al.Journal of Neuroinflammation2010,7:90 http://www.jneuroinflammation.com/content/7/1/90

JOURNAL OF NEUROINFLAMMATION

R E S E A R C HOpen Access Human intravenous immunoglobulin provides protection against Abtoxicity by multiple mechanisms in a mouse model of Alzheimer’s disease 1* 11 1 11 2 Johanna Magga, Lakshman Puli , Rea Pihlaja , Katja Kanninen , Suvi Neulamaa , Tarja Malm , Wolfgang Härtig , 2 11,3 1,4,51,6 Jens Grosche , Gundars Goldsteins , Heikki Tanila, Jari Koistinaho, Milla Koistinaho

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) againstbamyloid (Ab) 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 Abdeposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. Methods:We first determined the effect of IVIG on Abtoxicity in primary neuronal cell culture. The mechanisms ofaction of IVIG in reduction of Abburden was analyzed withex vivoassay. We studied whether IVIG solubilizes natively formed Abdeposits from brain sections of APP/PS1 mice or promotes Abremoval by primary glial cells. We determined the role of lysosomal degradation pathway and AbAbs in the IVIGpromoted reduction of Ab. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Abin a mouse model of ADin vivo. Results:IVIG was protective against Abtoxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Ab142 but did not solubilize natively formed brain Abdepositsex vivo. IVIG enhanced microgliamediated Abclearanceex vivo, with a mechanism linked to AbAbs and lysosomal degradation. The IVIGenhanced Abclearance appears specific for microglia since IVIG did not affect Abclearance by astrocytes. The cellular mechanisms of Abclearance we observed have potential relevancein vivosince after peripheral administration IVIG penetrated to mouse brain tissue reaching highest concentrations in the hippocampus and bound selectively to Abdeposits in colocalization with microglia. Conclusions:Our results demonstrate that IVIG promotes recognition and removal of natively formed brain Ab deposits by primary microglia involving natural AbAbs in IVIG. These findings may have therapeutic relevancein vivoas IVIG penetrates through the bloodbrain barrier and specifically binds to Abdeposits in brain parenchyma.

Background Deposition of Abpeptides is the major hallmark of AD in addition to neurofibrillary tangles formed by hyper phosphorylated tau [1]. The Abdeposits consist primar ily of fibrillized Ab140 and Ab142 peptides, the latter

* Correspondence: [e-mail] 1 Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland Full list of author information is available at the end of the article

being more prone to aggregation. The Abdeposits con taining Abpeptide oligomers, diffuse Abdeposits and aggregated fibrillar Abinduce neurotoxicity and cogni tive defects, as demonstratedin vitroandin vivo[14]. The Abneurotoxicity may be largely regulated by microglia, the surveillant cells of the CNS [5], which may possess doublefaced actions of conducting both proinflammatory and antiinflammatory effects [69].

© 2010 Magga et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.