Affiliations: [a] Protein Design and Immunotherapy Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Edifici C, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| [b] Departament de Biologia Cellular, de Fisiologia i d’Immunologia, Unitat de Citologia i d’Histologia, Facultat de Biociències, Edifici C, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| [c] Current address: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
Correspondence:
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Correspondence to: Sandra Villegas, Departament de Bioquímica i Biologia Molecular, Protein Design and Imunotherapy Group, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Tel.: +34 935814258; Fax: +34 935811264; E-mail: [email protected].
Abstract: The intracellular deposition of amyloid-β (Aβ) peptides has been described in the brains of both Alzheimer’s disease (AD) patients and animal models. A correlation between the intracellular amyloid burden and neurodegeneration has recently been reported in a triple-transgenic AD (3xTg-AD) murine model. In the present study, we assessed the effect of scFv-h3D6, an anti-Aβ single-chain variable fragment (scFv) derived from the antibody bapineuzumab, on amyloid pathology in 5-month-old 3xTg-AD female mice, focusing on intracellular Aβ clearance, neuronal survival, and functional abilities. We also examined neuroinflammation and the histology of peripheral organ samples to detect any adverse effects. A single intraperitoneal injection of scFv-h3D6 dramatically reduced intracellular Aβ burden in the deep layers of the cerebral cortex, pyramidal cells layer of the hippocampus, and basolateral amygdalar nucleus. The treatment prevented neuronal loss in the hippocampus and amygdala, while neither astrogliosis nor microgliosis was induced. Instead, an increase in the size of the white pulp after the treatment indicated that the spleen could be involved in the clearance mechanism. Although the treatment did not ameliorate behavioral and psychological symptoms of dementia-like symptoms, the results of cognitive testing pointed to a noticeable improvement in spatial memory. These findings indicated that the mechanism underlying the therapeutic effect of scFv-h3D6 was the clearance of intracellular Aβ, with subsequent prevention of neuronal loss and amelioration of cognitive disabilities. The treatment was safe in terms of neuroinflammation and kidney and liver function, whereas some effects on the spleen were observed.
