Naturally occurring autoantibodies interfere with β-amyloid metabolism and improve cognition in a transgenic mouse model of Alzheimer’s disease 24 h after single treatment

Abstract

There is evidence that naturally occurring antibodies directed against Aβ (nAbs-Aβ) have a role in Aβ-metabolism and Aβ-clearance. The presence of nAbs-Aβ leads to a reduction in amyloid fibrillation and thus a reduction in their toxicity. We investigated the effects of nAbs-Aβ in respect to oligomerization and used the Tg2576 transgenic mouse model in order to investigate the rapid effect with a single-dose (24 h) on oligomer breakdown and cytokine secretion along with immunohistochemical characterization of synaptic plasticity. nAbs-Aβ were able to reduce toxic oligomer concentration with an increase in Aβ-monomers. Cytokine secretion was significantly reduced. Synaptic plasticity was also improved after administration of nAbs. Finally, single treatment lead to a significant improvement in cognition. This study demonstrates the efficacy of nAbs-Aβ and presents evidence that several hallmarks of the disease are targeted by nAbs-Aβ.

A Human Monoclonal IgG That Binds Aβ Assemblies and Diverse Amyloids Exhibits Anti-Amyloid ActivitiesIn VitroandIn Vivo

“…The ability of the 3H3 mAb to inhibit their toxicity on a living brain demonstrates one mechanism whereby naturally occurring, conformation-specific antibodies in IVIG may exert a protective function in AD. Murine conformation-specific mAbs have also shown activity in the rat model of A␤ synaptotoxicity (Klyubin et al, 2008;.…”

“…Amyloid fibrils derived from AL patient tissues and AD patient brain plaque cores have been described previously (O'Nuallain et al, 2007;O'Nuallain et al, 2008).…”

“…Human intravenous Ig's (IVIGs) derived from pools of plasma from healthy donors contain IgGs that bind these epitopes (Du et al, 2001;Du et al, 2003;. We reported that A␤-reactive polyclonal IgGs in IVIGs cross-reacted with different types of amyloid fibrils and oligomers, including Ig light chain amyloid (AL) O'Nuallain et al, 2008). These antibodies impaired A␤ and AL fibrillogenesis in vitro and dissociated AL amyloid in vivo.…”

“…These antibodies impaired A␤ and AL fibrillogenesis in vitro and dissociated AL amyloid in vivo. Experiments testing IVIG in transgenic AD mouse models suggested that short-term or long-term treatments can benefit cognitive function (Mengel et al, 2013;St-Amour et al, 2014). Results of clinical testing of IVIG in mild to moderate AD patients have been mixed, but a randomized trial suggested cognitive benefits for moderate AD patients and APOE-4 carriers .…”

The Multi-target Effects of CNI-1493: Convergence of Antiamylodogenic and Antiinflammatory Properties in Animal Models of Alzheimer’s Disease

“…To investigate the treatment efficacy of C1213 on visuospatial learning and memory in TgCRND8 mice, we performed the object location test (OLT). The OLT is based on the spontaneous tendency of rodents to explore an object moved to a new location more often than an object located at a familiar position (25). Animals are exposed to two identical objects in an experimental apparatus and, after a delay, reexposed to the same two objects, one of which has been moved to a new location.…”