| Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting memory, thinking, behavior, and emotion. It is characterized by a progressive accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Evidence suggests that the deposition of amyloid triggers a cascade that ultimately leads to Alzheimer's pathology, making amyloid a promising target for the treatment of AD. Amyloid plaques are composed mainly of the 4.5 kD peptide fragment amyloid beta (Abeta). One strategy targeting Abeta is to deliver an Abeta binding agent outside the brain, creating a peripheral sink that causes efflux of Abeta across the blood-brain barrier.; One such agent is the 89 kD protein plasma gelsolin. However, administering such a large compound poses formidable formulations challenges, and proteins generally have poor pharmacokinetic properties. Taking a gene-therapy approach by delivering a DNA vector coding for plasma gelsolin offers an alternative to repeated injections of protein.; We developed a plasmid vector for human plasma gelsolin. We determined that plasma gelsolin may have enzymatic-like functions toward Abeta, shifting the equilibrium from fibrillization and deposition to solubilization and elimination. We obtained expression of our plasmid vector for plasma gelsolin in the periphery of 2 different mouse models of Alzheimer's, and showed that it results in a significant reduction in the amount of Abeta in the brain. We also showed that this reduction of Abeta in the brain may occur along with an increase in microglia activity. These results show the validity of using plasma gelsolin as a peripheral gene therapy of Alzheimer's disease. |
