A detergent-insoluble membrane compartment contains Aβ in vivo

Seung Jae Lee, Udaya Liyanage, Perry E. Bickel, Weiming Xia, Peter T. Lansbury, Kenneth S. Kosik

Research output: Contribution to journalArticle

354 Scopus citations

Abstract

Ordered assembly of the amyloid-β protein (Aβ) into amyloid fibrils is a critical step in Alzheimer's disease (AD). To release the amyloidogenic peptide Aβ from the Alzheimer amyloid precursor protein (APP), two secretases act sequentially: first, β-secretase cleaves close to the membrane within the ectodomain and then γ-secretase cuts within the transmembrane domain. The sites of γ-secretase cleavage are after residues 40 or 42 of Aβ. Except in those rare cases of AD caused by a mutation, levels of secreted Aβ are not elevated; thus, the secretory pathway may be unaffected, and factors other than the extracellular concentration of Aβ may contribute to the aggregation properties of the peptide. Aβ is also present in intracellular compartments. The two γ-secretase cleavage products, Aβ42 and Aβ40, were found in different compartments: Aβ42 in the endoplasmic reticulum (ER)/intermediate compartment, and Aβ40 in the trans-Golgi network (TGN). The cellular compartments that harbor Aβ are target sites for therapeutic intervention. Here we report that in the brain, the principal compartment in which Aβ resides is a detergent-insoluble glycolipid-enriched membrane domain (DIG). Also present in the DIG fractions are the endoproteolytic fragments of presenilin-1 (PS1) and APP. The presence of these proteins, which all contribute to the generation of Aβ, indicates that the DIG fraction is probably where the intramembranous cleavage of APP occurs.

Original languageEnglish (US)
Pages (from-to)730-734
Number of pages5
JournalNature medicine
Volume4
Issue number6
DOIs
StatePublished - Jun 1 1998

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lee, S. J., Liyanage, U., Bickel, P. E., Xia, W., Lansbury, P. T., & Kosik, K. S. (1998). A detergent-insoluble membrane compartment contains Aβ in vivo. Nature medicine, 4(6), 730-734. https://doi.org/10.1038/nm0698-730