Antibodies bound to Aβ oligomers potentiate the neurotoxicity of Aβ by activating microglia

Abstract

Beta amyloid (Ab) oligomers are thought to contribute to the pathogenesis of Alzheimer's disease. However, clinical trials using Ab immunization were unsuccessful due to strong brain inflammation, the mechanisms of which are poorly understood. In this study we tested whether monoclonal antibodies to oligomeric Ab would prevent the neurotoxicity of Ab oligomers in primary neuronal-glial cultures. However, surprisingly, the antibodies dramatically increased the neurotoxicity of Ab. Antibodies bound to monomeric Ab fragments were non-toxic to cultured neurons, while antibodies to other oligomeric proteins: hamster polyomavirus major capsid protein, human metapneumovirus nucleocapsid protein, and measles virus nucleocapsid protein, strongly potentiated the neurotoxicity of their antigens. The neurotoxicity of antibodyoligomeric antigen complexes was abolished by removal of the Fc region from the antibodies or by removal of microglia from cultures, and was accompanied by inflammatory activation and proliferation of the microglia in culture. In conclusion, we find that immune complexes formed by Ab oligomers or other oligomeric/ multimeric antigens and their specific antibodies can cause death and loss of neurons in primary neuronal-glial cultures via Fc-dependent microglial activation. The results suggest that therapies resulting in antibodies to oligomeric Ab or oligomeric brain virus proteins should be used with caution or with suppression of microglial activation.

Paeoniflorin attenuates Aβ1-42-induced inflammation and chemotaxis of microglia in vitro and inhibits NF-κB- and VEGF/Flt-1 signaling pathways

“…It has been demonstrated that Aβ oligomers not only induce the overproduction of pro-inflammatory mediators but also enhance the secretion of chemokines from microglia (Cai et al, 2014;Morkuniene et al, 2013), leading to destructive aggregation and chemotaxis of microglia in neuritic plaques of AD brains. Elevation of chemokines, such as CXCL-1 and CCL-2, accelerates the recruit of more microglia towards Aβ in brain (Tamura et al, 2005;Westin et al, 2012).…”

Specific Amyloid β Clearance by a Catalytic Antibody Construct

“…The A␤ species mass (monomers, oligomers, and proteolytic fragments) was computed by comparison with reference proteins (1.4 -27 kDa and 14 -97 kDa ladders; Bio-Rad). Oligomer disappearance was monitored by densitometry of the SDS-stable trimer, tetramer, and high mass oligomer bands (45 kDa band, 64 -84 kDa smear) following staining of gel blots with a mixture of mouse anti-A␤ monoclonal IgG 6E10, IgG 4G8 (both from Covance, Princeton, NJ), and IgG 6D4 (MyBioSource, San Diego, CA) (directed to A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), A␤ (17)(18)(19)(20)(21)(22)(23)(24), and the A␤ C terminus, respectively). Freshly dissolved A␤42 without prior oligomerization was mixed immediately with the nIgVs (3 g/ml) to test the nIgV effect on oligomer accumulation over 24 h of incubation at 4°C.…”

“…The EDTA-treated nIgV and aIgV 2E6 preparations without A␤ hydrolytic activity also failed to dissolve fibrillar A␤, suggesting catalysis as the dissolution mechanism. Enzymatic hydrolysis at the IgV-sensitive His 14 -Gln 15 bond was described to generate the soluble, non-amyloidogenic, and non-neurotoxic A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and A␤(15-42) fragments (35). A soluble peptide fragment with mass approximating that of the anticipated A␤(1-14) product was released upon nIgV 2E6 treatment of preformed fibrillar 125 I-A␤42 (Fig.…”

“…Such IgGs exert competing favorable and unfavorable effects (7,8). Whereas the A␤-IgG immune complexes are cleared via the Fc receptor-dependent uptake pathway by phagocytic cells (the microglia) (4), the activated cells release inflammatory mediators and neurotoxic factors (5,9). Moreover, A␤-binding monoclonal IgGs clear parenchymal A␤42, but they induce increased A␤40 deposition in blood vessel walls, enhancing the incidence of microhemorrhages and CAA (6,7) thought to be correlated with cognitive impairments (10).…”

Microglia as a critical player in both developmental and late-life CNS pathologies

“…Furthermore, oligomer-specific antibodies to Aβ lead to increased neurotoxicity of Aβ in a mixed culture of primary neuronal and glial cells. Both the depletion of the Fc region and the removal of microglia from the culture diminished this effect implicating microglia as a crucial mediator of neuronal death [86]. Inhibition of the Aβ–FcyR interaction could be a new therapeutic approach for AD and might bring a revival of immunization trials.…”