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

The accumulation and deposition of the 40-42-amino acid peptide amyloid beta ( A beta) is thought to be a critical event in the pathology of Alzheimer's disease ( AD). Both passive and active immunizations against A beta in amyloid-depositing transgenic mice have reduced A beta pathology and improved memory-related behavior. Peripheral treatments with other amyloid-binding agents have also reduced A beta pathology. The present study demonstrates that peripheral delivery of plasmid DNA coding for the amyloid-binding protein plasma gelsolin reduces brain A beta in two separate amyloid-depositing transgenic mouse models of AD when inter-litter variability is accounted for. The reduction in A beta 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 of AD.