Differential effects of apoE and apoJ mimetic peptides on the action of an anti-A beta scFv in 3xTg-AD mice
Por:
Montoliu-Gaya, L, Guell-Bosch, J, Esquerda-Canals, G, Roda, AR, Serra-Mir, G, Lope-Piedrafita, S, Sanchez-Quesada, JL, Villegas, S
Publicada:
1 sep 2018
Resumen:
Anti-A beta immunotherapy has emerged as a promising approach to treat Alzheimer's disease (AD). The single-chain variable fragment scFv-h3D6 is an anti-A beta antibody fragment that lacks the Fc region, which is associated with the induction of microglial reactivity by the full-length monoclonal antibody bapineuzumab. ScFv-h3D6 was previously shown to restore the levels of apolipoprotein E (apoE) and apolipoprotein J (apoJ) in a triple-transgenic-AD (3xTg-AD) mouse model. Since apoE and apoJ play an important role in the development of AD, we aimed to study the in vivo effect of the combined therapy of scFv-h3D6 with apoE and apoJ mimetic peptides (MPs). Four-and-a-half-month-old 3xTg-AD mice were treated for six weeks with scFv-h3D6, apoE-MP, apoJ-MP, or a combination of scFv-h3D6 with each of the MPs, or a vehicle, and then the results were compared to non-transgenic mice. Magnetic Resonance Imaging showed a general tendency of the different treatments to protect against the reduction in brain volume. All burden decreased after treatment with scFv-h3D6, apoE-MP, or apoJ-MP, but the effect was not as evident with the combined therapies. In terms of glial reactivity, apoE-MP showed a potent anti-inflammatory effect that was eased by the presence of scFv-h3D6, whereas the combination of apoJ-MP and scFv-h3D6 was not detrimental. ScFv-h3D6 alone did not induce microglial reactivity, as full-length antibodies do; rather, it reduced it. Endogenous apoE and apoJ levels were decreased by scFv-h3D6, but the MPs lead to a simultaneous increase of both apolipoproteins. While apoE-MP and apoJ-MP demonstrated different effects in the combined therapies with scFv-h3D6, they did not improve the overall protective effect of scFv-h3D6 in reducing the A beta burden, apolipoproteins levels or microglial reactivity.
Filiaciones:
Montoliu-Gaya, L:
Univ Autonoma Barcelona, Fac Biociencies, Dept Bioquim & Biol Mol, Prot Folding & Stabil Grp, E-08193 Barcelona, Spain
Guell-Bosch, J:
Univ Autonoma Barcelona, Fac Biociencies, Dept Bioquim & Biol Mol, Prot Folding & Stabil Grp, E-08193 Barcelona, Spain
Esquerda-Canals, G:
Univ Autonoma Barcelona, Fac Biociencies, Dept Bioquim & Biol Mol, Prot Folding & Stabil Grp, E-08193 Barcelona, Spain
Roda, AR:
Univ Autonoma Barcelona, Fac Biociencies, Dept Bioquim & Biol Mol, Prot Folding & Stabil Grp, E-08193 Barcelona, Spain
Serra-Mir, G:
Univ Autonoma Barcelona, Fac Biociencies, Dept Bioquim & Biol Mol, Prot Folding & Stabil Grp, E-08193 Barcelona, Spain
Lope-Piedrafita, S:
Univ Autonoma Barcelona, Serv Ressonancia Magnet Nucl, Cerdanyola Del Valles, Spain
Univ Autonoma Barcelona, Ctr Invest Biomed Red Bioingn Biomat & Nanomed CI, Cerdanyola Del Valles, Spain
Sanchez-Quesada, JL:
Res Inst Hosp St Pau JIB St Pau, Cardiovasc Biochem Grp, Barcelona, Spain
CIBER Diabet & Metab Dis CIBERDEM, Madrid, Spain
Villegas, S:
Univ Autonoma Barcelona, Fac Biociencies, Dept Bioquim & Biol Mol, Prot Folding & Stabil Grp, E-08193 Barcelona, Spain
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