Regulation of amyloid production by focused ultrasound

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PROJECT SUMMARY Beta amyloid (Aβ) is a protein that aggregates to form plaques associated with Alzheimer disease (AD). Its formation from amyloid precursor protein (APP) by hydrolytic enzymes beta and gamma secretases is regulated by brain cholesterol and depends on clustering of the proteins. In this application we propose to use focus ultrasound (FUS) to disrupt cholesterol’s clustering of APP and inflammatory regulators toll like receptor 4 (TLR4) and tumor necrosis factor alpha (TNF𝛼) which are also contributors to AD. We hypothesize, in that FUS can reverse the effects cholesterol in an AD brain. To test our hypothesis, we propose two specific aims. First, we will analyze clustering of amyloid proteins APP and gamma secretase with and without FUS using dSTORM super resolution imaging in a mouse model of AD. In a second aim we will characterize the de-clustering of inflammatory proteins TLR4 and TNF𝛼 in response to FUS also in an AD mouse model. The premise of this work is that cholesterol regulates nanoscopic trafficking of proteins in the membrane and FUS disrupts the trafficking. Completion of the studies establish a direct molecular mechanism for FUS independent of opening the blood brain barrier and FUS protocols with the potential to prevent or stop AD progression.