Mechanical forces and their cellular transducers have been linked to Alzheimer?s disease (AD), but mechanistic insights remain lacking. In our study of Piezo1, an important mam- malian mechanotransduction channel, we made the novel and unexpected finding that the levels of several enzymes involved in cholesterol biosynthesis are significantly re- duced in the developing mouse brain. Cholesterol metabolism is intimately connected to AD and very recent work using human induced pluripotent stem cells (hiPSCs)-derived neural cells suggested that levels of cholesterol and cholesteryl esters are central to fun- damental pathological changes associated with AD. We would like to therefore determine if the absence of Piezo1 would reduce cholesterol levels in neural cells derived from hiP- SCs from both control and AD-afflicted individuals (Aim 1). We would then further explore the impact of the lack of Piezo1 on AD pathology in these neural cells (Aim 2). Human iPSCs from individuals with familial or sporadic Alzheimer?s disease are available to us through the UCI Alzheimer?s Disease Research Center (ADRC), and these will be engi- neered using CRISPR/Cas9 to delete Piezo, and then differentiated into neurons and glia. This approach using isogenic lines will shed light on the role of Piezo1 in cholesterol metabolism in the context of AD. If successful, this work would provide a potential target to modulate cholesterol metabolism and prevent the progression of AD.
The supplement instructions PA?18?591 state: ?At minimum, the Research Strategy section should be completed and must include a summary or abstract of the funded parent award or project. Other sections should also be included if they are being changed by the proposed supplement activities.? The original Project Narrative has not changed as a result of the proposed supplement activities.