Aß-oligomer uptake and the resulting inflammatory response in adult human astrocytes are precluded by an anti-Aß single chain variable fragment in combination with an apoE mimetic peptide.

ABSTRACT

An imbalance between production and clearance of soluble amyloid-ß (Aß) initiates the pathological process in sporadic Alzheimer's disease (AD). Aß-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Aß-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered. To prevent inflammatory reactions, we designed a single chain variable fragment (scFv-h3D6), based on monoclonal antibody bapineuzumab (mAb-h3D6), but lacking the Fc region. ScFv-h3D6 reduced Aß-oligomer burden and prevented AD-associated behavioral and cellular changes in 3xTg-AD mice. As scFv-h3D6 lacks the Fc-tail, it cannot enhance Fc-receptor mediated Aß clearance by microglia and probably exerts its beneficial effects in 3xTg-AD mice through other mechanisms. ScFv-h3D6 restored the increased apoE and apoJ levels in 3xTg-AD brains back to normal. ApoE and apoJ influence cholesterol transport, Aß aggregation and clearance, and their genetic variants are risk factors for sporadic AD. Astrocytes are constitutive scavengers of soluble Aß from the CNS. We previously found apoE and apoJ to inhibit Aß uptake by adult human astrocytes, in vitro, and thus to potentially protect astrocytes from Aß cytotoxicity. In the present study, scFv-h3D6 and mAb-h3D6 inhibited Aß-oligomer uptake by adult human astrocytes. ApoE- and apoJ- mimetic peptides (MP) affected Aß uptake as well as Aß-induced cytokine release similar to intact apoE and apoJ, without interfering with the strong inhibitory effects of scFv-h3D6 on Aß-oligomer uptake. These results suggest that combining Aß-specific scFv and apoE-MP, that inhibits Aß oligomer-induced cytokine release by astrocytes, could offer advantages over currently used therapeutics.