Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Alzheimer's disease (AD) is characterized by progressive neuron loss due to the aggregation of toxic amyloid-beta (Ab) peptides. Many anti-Ab therapies currently being investigated aim to clear Ab from the brain, thus halting neurodegeneration. These treatments, however, are still in the developmental stages and face major challenges. A major limitation of anti-Ab antibody therapy in AD is that only 0.1-1% of systemic administered antibodies will cross the blood-brain barrier (BBB) to enter the brain. For safety reasons, the amount of antibodies in the bloodstream must remain reasonably low to minimize side effects. To improve safety and efficiency of treatments, we propose to use magnetic resonance imaging-guided focused ultrasound (MRIgFUS) to deliver systemically injected anti-Ab antibodies to the brain. MRIgFUS, in combination with clinically-used microbubble ultrasound contrast agent, has been shown to disrupt the BBB in a non-invasive, transient and localized manner. BBB permeability is temporarily increased when ultrasound waves cause the microbubbles to resonate and come into contact with the cell membranes of blood vessels. I have demonstrated the ability to deliver anti-Ab antibody to the brain of an Alzheimer's mouse model using MRIgFUS and reduce the number of Ab plaques by 4 days after a single treatment. I plan to test longer term treatment strategies to completely clear Ab loads using MRIgFUS technology in two preclinical mouse models of AD - 3xTg-AD mice and TgCRND8 mice. These two treatment paradigms in TgCRND8 and 3xTg-AD mice represent models of treatment strategies at late (with plaques) and early (no plaque, just soluble Ab) stages of AD pathology, respectively. The use of MRIgFUS to deliver Ab antibodies directly into the brain has great potential at increasing efficacy of treatment with lower amounts of systemic antibodies, minimizing Ab toxicity in the brain and reducing the chances of detrimental side effects following therapy.