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

Abstract

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 beta-amyloid (Abeta) 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 Abeta deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses.

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

RESULTS: IVIG was protective against Abeta toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Abeta1-42 but did not solubilize natively formed brain Abeta deposits ex vivo. IVIG enhanced microglia-mediated Abeta clearance ex vivo, with a mechanism linked to Abeta Abs and lysosomal degradation. The IVIG-enhanced Abeta clearance appears specific for microglia since IVIG did not affect Abeta clearance by astrocytes. The cellular mechanisms of Abeta 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 Abeta deposits in co-localization with microglia.

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