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

An imbalance between production and clearance of soluble amyloid-beta (A beta) initiates the pathological process in sporadic Alzheimer's disease (AD). A beta-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and A beta-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 A beta-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 AP 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, A beta aggregation and clearance, and their genetic variants are risk factors for sporadic AD. Astrocytes are constitutive scavengers of soluble A beta from the CNS. We previously found apoE and apoJ to inhibit A beta uptake by adult human astrocytes, in vitro, and thus to potentially protect astrocytes from A beta) cytotoxicity. In the present study, scFv-h3D6 and mAb-h3D6 inhibited A beta-oligomer uptake by adult human astrocytes. ApoE- and apoJ-mimetic peptides (MP) affected A beta uptake as well as A beta-induced cytokine release similar to intact apoE and apoJ, without interfering with the strong inhibitory effects of scFv-h3D6 on A beta-oligomer uptake. These results suggest that combining A beta-specific scFv and apoE-MP, that inhibits A beta oligomer-induced cytokine release by astrocytes, could offer advantages over currently used therapeutics.