Abstract
Intravenous Immunoglobulin (IVIG) has been proposed as a potential therapeutic for Alzheimer's disease (AD) and its efficacy is currently being tested in mild-to-moderate AD. Earlier studies reported the presence of anti-amyloid beta (Aβ) antibodies in IVIG. These observations led to clinical studies investigating the potential role of IVIG as a therapeutic agent in AD. Also, IVIG is known to mediate beneficial effects in chronic inflammatory and autoimmune conditions by interfering with various pathological processes. Therefore, we investigated the effects of IVIG and purified polyclonal Aβ -specific antibodies (pAbs-Aβ) on aggregation, toxicity and phagocytosis of Aβ in vitro, thus elucidating some of the potential mechanisms of action of IVIG in AD patients. We report that both IVIG and pAbs-Aβ specifically bound to Aβ and inhibited its aggregation in a dose-dependent manner as measured by Thioflavin T assay. Additionally, IVIG and the purified pAbs-Aβ inhibited Aβ-induced neurotoxicity in the SH-SY5Y human neuroblastoma cell line and prevented Aβ binding to rat primary cortical neurons. Interestingly, IVIG and pAbs-Aβ also increased the number of phagocytosing cells as well as the amount of phagocytosed fibrillar Aβ by BV-2 microglia. Phagocytosis of Aβ depended on receptor-mediated endocytosis and was accompanied by upregulation of CD11b expression. Importantly, we could also show that Privigen dose-dependently reversed Aβ-mediated LTP inhibition in mouse hippocampal slices. Therefore, our in vitro results suggest that IVIG may have an impact on different processes involved in AD pathogenesis, thereby promoting further understanding of the effects of IVIG observed in clinical studies.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the aging population
Characterization of Ab preparations To ensure consistent quality of the oligomer preparations used, these preparations were continuously controlled by Western Blot analysis and Atomic Force Microscopy (AFM)
The cross-linking had only a small effect on the fibrils. It resulted in the stabilization of the fibril and only very few Ab monomers remained (f*), whereas the proportion of free monomers was much larger in non-crosslinked fibrils (f), since monomers are in constant equilibrium with fibrils
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the aging population. A Phase II study in a small number of AD patients showed maintenance of cognitive function in subjects treated with 0.4 g IVIG/kg/2weeks [7]. A small prospective clinical trial of IVIG therapy in AD patients, showed that IVIG-treatment increased Ab in serum and decreased Ab in CSF, and maintained cognitive function as compared to salinetreated control AD patients [8]. Another phase II dose-finding trial of IVIG for treatment of mild-moderate AD found significantly increased plasma Ab40 in the 0.4 g/kg every two weeks patient group compared to placebo group [9]
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