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Can promoting the brain’s ability to clear unwanted proteins help prevent brain changes linked to Alzheimer’s?
Zoltan Arany, M.D., Ph.D.
University of Pennsylvania
Philadelphia, PA - United States
Background
Unusable or damaged proteins in cells are broken down and transported out of the cell through a tightly regulated process that includes several compartments called lysosomes within the cell that help degrade and dispose of a cell’s waste. Studies have shown that lysosomes become damaged in brain diseases, including Alzheimer’s, and this damage may hinder the brain’s ability to clear abnormal proteins, such as beta-amyloid plaques and tau tangles, two hallmark brain changes associated with Alzheimer’s, that accumulate during disease.
Studies have found that a biological pathway initiated by a group of proteins known as mTORC1 (mammalian target of rapamycin complex 1) can damage lysosomes and hinder the cellular transport system. These results have led researchers to test whether reducing mTORC1 activity can promote the clearance of beta-amyloid and tau and whether it has an impact on cognition. However, reducing mTORC1 activity broadly is also not ideal as mTORC1 carries out several vital functions in all cells, including processes linked to cellular growth and energy generation. Inhibiting all of mTORC1’s functions may result in harmful side effects in living brains. Scientists must develop a way of inhibiting only those functions of mTORC1 that impact the transport system specifically.
Research Plan
In initial research with brain cells grown in a laboratory dish and with genetically engineered Alzheimer’s-like mice, Dr. Zoltan Arany and colleagues studied a protein component of mTORC1 called FLCN (folliculin). Their results showed that this protein could inhibit lysosomes and the cellular transport system, but not impact other mTORC1 functions. Targeting FLCN, therefore, might be an effective and safe way to prevent mTORC1 from promoting the spread of abnormal proteins in Alzheimer’s disease.
Dr. Arany and team will conduct a larger study to assess the value of targeting this biology as a possible therapy target. First, they will confirm whether deleting FLCN can promote the health and function of lysosomes and the overall transport system in laboratory brain cells and Alzheimer’s-like mice. They will also investigate the role of these models on mTORC1 activity and function. They will then test whether changing the expression of FLCN has an impact on tau build up and impacts the learning and memory in the Alzheimer’s-like mice.
Impact
Dr. Arany’s project could shed new light on how the process of cellular transport and clearance may be impacted in Alzheimer’s disease. It could also identify a novel method for blocking the protein accumulations linked to dementia.
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