IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease.

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aß autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Sträussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120 days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases.

The role of choroid plexus in IVIG-induced beta-amyloid clearance.

We have shown that intravenous immunoglobulin (IVIG) contains anti-Aß autoantibodies and IVIG could induce beta amyloid (Aß) efflux from cerebrospinal fluid (CSF) to blood in both Multiple Sclerosis (MS) and Alzheimer disease (AD) patients. However, the molecular mechanism underlying IVIG-induced Aß efflux remains unclear. In this study, we used amyloid precursor protein (AßPP) transgenic mice to investigate if the IVIG could induce efflux of Aß from the brain and whether low-density lipoprotein receptor-related protein-1 (LRP1), a hypothetic Aß transporter in blood-CSF barrier (BCB); could mediate this clearance process. We currently provide strong evidence to demonstrate that IVIG could reduce brain Aß levels by pulling Aß into the blood system in AßPP transgenic mice. In the mechanistic study, IVIG could induce Aß efflux through the in vitro BCB membrane formed by cultured BCB epithelial cells. Both receptor-associated protein (RAP; a functional inhibitor of LRP1), and LRP1 siRNA were able to significantly inhibit the Aß efflux. Should Aß prove to be the underlying cause of AD, our results strongly suggest that IVIG could be beneficial in the therapy for AD by inducing efflux of Aß from the brain through the LRP1 in the BCB.