Peripheral transgene expression of plasma gelsolin reduces amyloid in transgenic mouse models of Alzheimer's disease

Abstract

The accumulation and deposition of the 40-42-amino acid peptide amyloid β(Aβ) is thought to be a critical event in the pathology of Alzheimer's disease (AD). Both passive and active immunizations against Aβ in amyloid-depositing transgenic mice have reduced Aβ pathology and improved memory-related behavior. Peripheral treatments with other amyloid-binding agents have also reduced Aβ pathology. The present study demonstrates that peripheral delivery of plasmid DNA coding for the amyloid-binding protein plasma gelsolin reduces brain Aβ in two separate amyloid-depositing transgenic mouse models of AD when inter-litter variability is accounted for. The reduction in Aβ pathology observed is accompanied by an apparent increase in activated and reactive microglia and soluble oligomeric forms of amyloid. These findings demonstrate that peripheral expression of plasma gelsolin may be a suitable gene-therapeutic approach for the prevention or treatment.