Active immunization strategies using different forms of Aβ have been extensively tested in amyloid precursor protein (APP) transgenic mouse models. The initial animal results were promising [
3,
4], but since active immunization in AD patients was associated with considerable side effects [
5] and some patients did not develop Aβ-antibody titers [
6], passive immunization strategies came into focus. Treatment with humanized monoclonal antibodies [
7] as well as passive immunization with intravenous immunoglobulins (IVIg) has been investigated in pilot clinical trials [
8,
9]. The rationale for its use is that IVIg contain naturally occurring autoantibodies against Aβ (nAbs-Aβ). Naturally occurring autoantibodies in the central nervous system are involved in maintaining homeostasis by removing debris and are known to prevent inflammation [
10]. The beneficial effects of nAbs-Aβ have been shown both
in vitro on primary neurons and neuronal cell lines as well as
in vivo in transgenic mice [
11,
12]. The effect of IVIg on microglial cells has already been investigated by other groups. It has been shown that IVIg reduce phagocytosis
in vitro via Fc receptors [
13], IVIg induce tumor necrosis factor-α (TNF-α) and nitric oxide (NO) in a dose-dependent manner, whereas the greater the IgM/IgA content the higher the impact on microglial cells [
14], and that IVIg enhance the secretion of matrix metalloproteinase 9, which seems to play a role in the pathogenesis of multiple sclerosis [
15]. Referring to Aβ, Magga
et al. found an increase in Aβ clearance when they administered IVIg in a dose-dependent manner on primary microglial cells [
16]. IVIg depleted of nAbs-Aβ did not promote clearance, indicating that the enhanced clearance effect is mediated by nAbs-Aβ. In a study on the immortalized murine microglial cell line BV-2, administration of IVIg restored cells’ viability and enhanced phagocytotic ability of fibrillar Aβ [
17]. In addition to these results, IVIg are limited in their availability and we therefore decided to use nAbs-Aβ in our study. Theoretically, these will be able to be cloned eventually and therefore the problem of availability can be overcome. In all experiments we used the negative fraction of IVIg, which contains all antibodies except those that were purified with the affinity chromatography, and we were not able to see the same effects as those obtained with nAbs-Aβ, coming to the conclusion that nAbs-Aβ are the active substance in IVIg responsible for the beneficial effects with regard to AD. The effect and the interaction, however, of nAbs-Aβ on microglial cells have not been investigated to date. This is especially important as microglia are purported to have a major role in the pathogenesis and propagation of AD [
18]. Upon stimulation, microglial cells can react in many different ways, including phagocytosis, the secretion of immunomodulating cytokines and finally programmed cell death in order to kill pathogens or restore tissue integrity [
19]. Activated microglial cells have been found surrounding plaques in histopathological sections of AD patients [
20] and their role in the phagocytosis of all forms of Aβ has been investigated. Due to the immune-stimulating effect of foreign monoclonal antibodies in the human body, we were interested in the effect of nAbs-Aβ on primary microglial cells. In the following experiments we investigated the effect of nAbs-Aβ on Aβ-treated microglial cells with respect to cell viability, neuroinflammation and phagocytosis, and whether any effect on primary neurons is conveyed by treated microglial cells.