Intravenous Immunoglobulin (IVIG) has been proposed like a potential restorative for Alzheimer’s disease (AD) and its efficacy is currently being tested in mild-to-moderate AD. amyloid-beta (A) peptide and its toxic aggregates is definitely thought to be the initiating event that is followed by synaptic dysfunction, swelling and eventually neuronal death [1], [2]. Therefore, several strategies to prevent A aggregation and toxicity are currently analyzed for potential therapy of TR-701 AD. Immunotherapy with monoclonal anti-A antibodies shown activity in transgenic TR-701 mouse models [3], [4] and a variety of anti-A antibodies are currently explored as potential therapeutics for AD [5]. The Phase III clinical tests for the monoclonal antibodies Bapineuzumab (J&J/Pfizer) and Solanezumab (Eli Lilly) have recently been completed and for both it was reported that the primary endpoints, cognitive and practical, were not met. Also, a polyclonal intravenous immunoglobulin (IVIG) preparation (Gammagard liquid; Baxter) is still in clinical Phase III tests (ClinicalTrials.gov). Gammagard liquid along with other IVIG products are commercial preparations of purified human being IgG manufactured from pooled plasma from thousands of donors [6]. 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]. The prolonged Phase II exposed that those who were treated with 0.4 g IVIG/kg/2 weeks for the full 36 months had the best outcome, with no decline in standard cognitive checks (Relkin et al., Alzheimer’s Dementia 2012; 8(4) Product, P589). A small prospective medical trial of IVIG therapy in AD patients, showed that IVIG-treatment improved A in serum and decreased A in CSF, and managed cognitive function as compared to saline-treated control AD individuals [8]. Another phase II dose-finding trial of IVIG for treatment of mild-moderate AD found significantly improved plasma A40 in the 0.4 g/kg every two weeks patient group compared to placebo group [9]. Organic, polyclonal anti-A antibodies have been detected in various IVIG preparations [6], [10]. Consequently, one of the potential mechanisms of action proposed for IVIG in AD is the direct binding of A by natural anti-A antibodies. However, additional possible mechanisms relate to the immunomodulatory and anti-inflammatory effects of IVIG [11]. Neuroinflammation characterized by triggered microglia and upregulation of a variety of inflammatory mediators, such TR-701 as cytokines, chemokines and reactive oxygen species (ROS), is a prominent feature of AD [12]. Therefore, IVIG might also influence inflammatory processes in the brain including modulation of microglial activation and increase of microglial phagocytosis of fibrillar A [13], [14]. Furthermore, we found that, apart from anti-A antibodies, IVIG consists of antibodies against additional disease-relevant proteins, such as Tau, pTau, RAGE and PrPc (Schaub et al., Neurodegenerative Dis. 2011; 7(4) Product, Page S670). Consequently, in contrast to monoclonal antibodies that identify only Rabbit polyclonal to IL1B. one specific linear or conformational epitope inside a and polyclonal anti-A antibodies that identify a variety of different linear and conformational epitopes inside a [15] IVIG identify several different potentially disease relevant focuses on [16]. This suggests IVIG could be a encouraging restorative for any multifactorial disease such as AD. In the current study we demonstrate the IVIG preparation Privigen and the purified pAbs-A both bound specifically to A, inhibited A-aggregation and A-mediated toxicity. Both preparations prevented the binding of A to main cortical neurons and improved the phagocytosis of fibrillar A by BV-2 cells, which correlated with increased expression of CD11b. In addition, Privigen completely reversed A-mediated LTP inhibition in mouse hippocampal slices. Our results indicate that IVIG could have the potential to improve certain AD related pathologies by multiple mechanisms. Materials and Methods IVIG preparations For those assays with this study the IVIG product Privigen?.