Research Description

Effect of Gelsolin on Aβ Plaques in APP/PS-1 Transgenic Mice

With an increase in human life expectancy, Alzheimer’s disease (AD) is becoming an ever-increasing burden to society, mandating that new therapies be developed and evaluated.

AD is characterized in part by the presence of extracellular amyloid plaques in the brain, composed mainly of the 40-42 amino acid peptide fragment amyloid beta (Aβ).

We hypothesize that the removal of Aβ peptides from systemic circulation will result in a decrease in brain Aβ concentrations and consequently plaques, potentially reversing some of the detrimental consequences of advanced diseases.

Our hypothesis is that we can increase the transport of Aβ from the brain into periphery by using a gene delivery approach to increase a protein (gelsolin) in the blood to bind Aβ. Plasma gelsolin is a highly conserved 83 kD actin-binding protein. Chauhan et al. demonstrated that plasma gelsolin binds to Aβ, prevents fibrillization, and disassembles preformed Aβ fibrils, suggesting a possible role for gelsolin in Aβ clearance. Matsuoka also demonstrated that injections of gelsolin can prevent deposition of Aβ in younger APP/PS-1 mice (a transgenic model of Aβ overprocution). Recent data suggest that after Aβ synthesis in the central nervous system (CNS), the peptide can be locally metabolized or cleared into the plasma. Thus, a lowering of free amyloid fragments in the plasma should result in a decrease of plaque formation given the fact there is an established transport system through the BBB for amyloid fragments.

To test our hypothesis, radio-labeled amyloid fragments will be administered to APP/PS-1 transgenic mice either in the lateral brain ventricle or via systemic administration. The administration will be conducted either in the presence or absence of peripheral gelsolin and the transport kinetics of the Aβ fragments quantified in both directions across the BBB. In this aim we will use recombinant human gelsolin protein, administering at increasing doses and monitoring Aβ fragment transport.