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

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 (A beta) 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 beta 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 beta toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of A beta burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed A beta deposits from brain sections of APP/PS1 mice or promotes A beta removal by primary glial cells. We determined the role of lysosomal degradation pathway and A beta Abs in the IVIG-promoted reduction of A beta. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human A beta in a mouse model of AD in vivo. Results: IVIG was protective against A beta toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic A beta 1-42 but did not solubilize natively formed brain A beta deposits ex vivo. IVIG enhanced microglia-mediated A beta clearance ex vivo, with a mechanism linked to A beta Abs and lysosomal degradation. The IVIG-enhanced A beta clearance appears specific for microglia since IVIG did not affect A beta clearance by astrocytes. The cellular mechanisms of A beta 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 beta deposits in co-localization with microglia. Conclusions: Our results demonstrate that IVIG promotes recognition and removal of natively formed brain A beta deposits by primary microglia involving natural A beta Abs in IVIG. These findings may have therapeutic relevance in vivo as IVIG penetrates through the blood-brain barrier and specifically binds to A beta deposits in brain parenchyma.