APP and Bace1: Differential effect of cholesterol enrichment on processing and plasma membrane mobility

Year: 2023

Authors: Capitini C., Bigi A., Parenti N., Emanuele M., Bianchi N., Cascella R., Cecchi C., Maggi L., Annunziato F., Pavone FS., Calamai M.

Autors Affiliation: Univ Firenze, Dipartimento Fis & Astron, I-50019 Florence, Italy; Univ Florence, European Lab Nonlinear Spect LENS, I-50019 Florence, Italy; Univ Florence, Dept Expt & Clin Biomed Sci, I-50134 Florence, Italy; Univ Florence, Dept Expt & Clin Med, I-50134 Florence, Italy; Natl Res Council Italy CNR, Natl Inst Opt, Largo Fermi 6, I-50125 Florence, Italy.

Abstract: High cholesterol levels are a risk factor for the development of Alzheimer’s dis-ease. Experiments investigating the influence of cholesterol on the proteolytic processing of the amyloid precursor protein (APP) by the b-secretase Bace1 and on their proximity in cells have led to conflicting results. By using a fluores-cence bioassay coupled with flow cytometry we found a direct correlation between the increase in membrane cholesterol amount and the degree of APP shedding in living human neuroblastoma cells. Analogue results were obtained for cells overexpressing an APP mutant that cannot be processed by alpha-secretase, highlighting the major influence of cholesterol enrichment on the cleavage of APP carried out by Bace1. By contrast, the cholesterol content was not correlated with changes in membrane dynamics of APP and Bace1 analyzed with single molecule tracking, indicating that the effect of cholesterol enrichment on APP processing by Bace1 is uncoupled from changes in their lateral diffusion.

Journal/Review: ISCIENCE

Volume: 26 (5)      Pages from: 106611-1  to: 106611-22

More Information: We acknowledge Perttu Terho the Cell Imaging and Cytometry core and Biocenter Finland, and Biorender. We thank Prof. Marco Cecchini and Dr. Ambra del Grosso for technical support. The Research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant Agrement n. PIEF-GA-2009-254791, by European Union’s Horizon 2020 research and innovation program under grant agreement No 654148Laserlab-Europe, and by Dept. of Experimental and Clinical Medicine and Department of Experimental and C linical Biomedical Sciences of University of Florence (ex -60%) derived from Ministero dell’Istruzione, dell’Universitae della Ricerca (Italy).
KeyWords: Amyloid Precursor Protein; Alpha-secretase Cleavage; Lateral Diffusion; A-beta; Tracking; Surface; Pathogenesis; Confinement; Metabolism; Retention
DOI: 10.1016/j.isci.2023.106611

Citations: 6
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