APP’s Function in Cholesterol Homeostasis Revealed through
Light Sheet Microscopy
Alzheimer’s Disease (AD) is characterized by progressive loss of neuronal function over time and with age. The amyloid hypothesis refers to the idea that the accumulation of amyloid beta (Aꞵ) plaque, derived from the transmembrane protein amyloid precursor protein (APP), is the cause of AD. Recent studies suggest that AD may not be caused by Aꞵ plaque, but instead the loss of APP. APP’s function is currently unclear, but previous research has demonstrated its association with cholesterol homeostasis. High density lipoproteins (HDLs) contribute to maintaining proper cholesterol concentrations in different parts of the brain. Because there are higher amounts of cholesterol within the nerve membrane than endocytic compartments, and these compartments show higher levels of Aꞵ compared to the membrane, APP is hypothesized to cause a lack of expression and distribution of HDLs and therefore the deregulation of cholesterol, which explains the neurodegeneration characteristic in Alzheimer’s patients. Using a novel tissue clearing and imaging technique, iDISCO and light sheet imaging, murine brains (WT and APP△) were immunolabeled with SREBP-2(1C6), a mouse monoclonal antibody to the SREBP-2 lipoprotein receptor, to compare changes in protein expression and further understanding of the function of APP. Significant results were observed in the hippocampus, but not in the other areas examined. Future steps include modifications to the antibodies and procedures to clarify results. Confirmation of the hypothesis on the role of APP in cholesterol homeostasis would contribute to an understanding of AD etiology and development of new therapeutics to treat AD.
Hadley is a motivated student that focuses a significant amount of her time on the PC Science Research Program. Her favorite subjects are math and science and she is president elect of the Women in STEM club. After high school, Hadley wants to continue her work in research at the university level.