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The role of cholesterol trafficking in BACE‐1 and APP co‐localization
Author(s) -
Levitt Claire Hoa,
Tarren Anna,
Cluett Edward
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.655.6
Subject(s) - amyloid precursor protein , amyloid precursor protein secretase , endosome , chemistry , cholesterol , alpha secretase , cleavage (geology) , microbiology and biotechnology , phospholipase a2 , pathogenesis , biochemistry , amyloid beta , enzyme , intracellular , alzheimer's disease , peptide , biology , medicine , disease , paleontology , fracture (geology)
Beta amyloid (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease (AD). Aβ peptides are derived from the processing of amyloid precursor protein (APP). This protein undergoes extensive processing involving two different pathways that produces several fragments. The α‐secretase pathway produces normal peptides. The pathogenic form of Aβ is derived from a cleavage product generated by beta‐site APP Cleaving Enzyme 1 (BACE‐1) that is then cleaved by γ‐secretase. Although the interaction of APP and BACE‐1 is critical for understanding how AD occurs, it is not clear how or where this occurs. Cholesterol has been identified as a risk factor in AD, and in vitro studies suggest that increased cholesterol levels promote misprocessing of APP. Our lab found that phospholipase A2 inhibitors, which inhibit the formation of membrane tubules, caused the accumulation of cholesterol in the recycling endosome in HeLa cells grown in moderate levels of LDL. APP also co‐localized to this compartment, and immunoblotting showed that the processing of APP and the association of APP fragments with cholesterol‐rich domains was altered by treatment with ONO‐RS‐082, a PLA2 inhibitor. However, BACE‐1 did not co‐localize with APP under these conditions. Surprisingly, in SY‐SH5Y cells co‐localization with BACE‐1 and APP did occur when cells were grown in low levels of LDL, which promote the synthesis of cholesterol. Using immunofluorescence/confocal microscopy and immunoblotting, we are confirming these results and extending this research by investigating the effects of statins or increased LDL on the localization and processing of these proteins. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .