How does a genetic variation impact the functioning of key types of brain cells in Alzheimer’s?
Brooke Alisen DeRosa, Ph.D.
Miller School of Medicine of the University of Miami
Miami, FL - United States
The endolysosomal system is a complex system responsible for sorting, breaking down, and removing unwanted materials in cells. When this system becomes impaired, the brain may lose its ability to dispose of unwanted proteins efficiently, which can lead to the build-up of disease-related molecules. Studies show that endolysosomal dysfunction may be associated with the accumulation of beta-amyloid plaques and tau tangles, the two main hallmark brain changes observed in Alzheimer’s.
The gene SORL1 is critical to the proper functioning of the endolysosomal system. SORL1 is active in two important cell types in the brain: nerve cells and microglia, which are the resident immune cells of the brain. However, it is not known how variations in the SORL1 gene may impact endolysosomal dysfunction and specifically affect nerve cells and microglia in Alzheimer’s.
Dr. Brooke DeRosa and colleagues will study the role SORL1 plays in Alzheimer’s-related endolysosomal dysfunction in nerve cells and microglia. The researchers will use a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body and grown in laboratory dishes. The iPSCs used for this study will be collected from cells of individuals with familial Alzheimer’s, a rare inherited form of the disease in which symptoms usually develop in one’s forties. These individuals also carry a rare variation of the SORL1 gene. The iPSCs will be reprogrammed into nerve cells and microglia. They will study these cells in laboratory dishes, first characterizing the impact of the SORL1 genetic variation on endolysosomal functioning in nerve cells and microglia individually. The researchers will also investigate how interactions between nerve cells and microglia may impact Alzheimer’s-related brain changes in endolysosomal functioning.
These findings may shed light on the underlying genetic mechanisms of certain Alzheimer’s-related brain changes. They may also identify novel avenues for future therapeutic research.
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