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P1‐479: Functional disorders of the lysosome reduces amyloid‐beta protein production
Author(s) -
Osawa Tenshi,
Yamazaki Tsuneo,
Okamoto Koichi
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1062
Subject(s) - lamp1 , filipin , lysosome , chinese hamster ovary cell , endosome , intracellular , biology , microbiology and biotechnology , secretion , endocytosis , biochemistry , chemistry , cell , cholesterol , receptor , enzyme
It has been well documented that apoE inhibits Abeta fibril formation in vitro especially in the nucleation phase, although the isoform-specific effects of apoE against Abeta fibrillization has not been well characterized. Methods: To evaluate the isoform-specific effects of apoE, we carried out an in vitro Abeta fibrillization assay and investigated the formation of low molecular weight Abeta, protofibrils, and fibrils using thioflavin T fluorescence and size exclusion chromatography. Results: First, we showed that Abeta(1-42) fibrillized faster in the presence of recombinant apoE4 than apoE2 or apoE3, although the affinity of the three isoforms to native Abeta were at similar levels. We next found that apoE2 and apoE3 enhanced the persistence of Abeta protofibrils and delayed the start of Abeta fibril formation, whereas apoE4 did not. We also found that protofibrils comprised of Abeta and apoE3 were more stable than those of Abeta and apoE4. In addition, a SDS-stable 40-kDa band positive both for Abeta and apoE was detected in the Abeta protofibril fraction upon coincubation with apoE2 or apoE3, which was scarcely detected with apoE4. Conclusions: These data suggest that apoE2/3 is involved in the stability of Abeta protofibrils, whereas apoE4 lacks this ability. The isoform-specific effects of apoE on Abeta protofibrils may be one of the determinants for the aggregation and deposition of Abeta in AD brains.