Influence of Lentiviral β-Synuclein Overexpression in the Hippocampus of a Transgenic Mouse Model of Alzheimer's Disease on Amyloid Precursor Protein Metabolism and Pathology

Abstract

Background: β-Synuclein (β-Syn) is a member of the highly homologous synuclein protein family. The most prominent family member, α-synuclein (α-Syn), abnormally accumulates in so-called Lewy bodies, one of the major pathological hallmarks of α-synucleinopathies. Notably, parts of the peptide backbone, called the nonamyloid component, are also found in amyloid plaques. However, β-Syn seems to have beneficial effects by reducing α-Syn aggregation, and amyloid antiaggregatory activity has been described. Objective: The aim of the study was to analyze if wild-type β-Syn can counteract functional and pathological changes in a murine Alzheimer model over different time periods. Methods: At the onset of pathology, lentiviral particles expressing human β-Syn were injected into the hippocampus of transgenic mice overexpressing human amyloid precursor protein with Swedish and London mutations (APP_SL). An empty vector served as the control. Behavioral analyses were performed 1, 3 and 6 months after injection followed by biochemical and histological examinations of brain samples. Results: β-Syn expression was locally concentrated and rather modest, but nevertheless changed its effect on APP expression and plaque load in a time- and concentration-dependent manner. Interestingly, the phosphorylation of glycogen synthase kinase 3 beta was enhanced in APP_SL mice expressing human β-Syn, but an inverse trend was observed in wild-type animals. Conclusion: The initially reported beneficial effects of β-Syn could be partially reproduced, but locally elevated levels of β-Syn might also cause neurodegeneration. To enlighten the controversial pathological mechanism of β-Syn, further examinations considering the relationship between concentration and exposure time of β-Syn are needed.