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A detergent-insoluble membrance compartment contains Aβ in vivo

Nature Medicine volume 4, pages 730–734 (1998)Cite this article

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 domain1. 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 compartments2–5. The two γ-secretase cleavage products, Aβ42 and Aβ40, were found in different compartments: Aβ42 in the endoplasmic reticulum (ER)/intermediate compartment3–5, and Aβ40 in the trans-Colgi network2,4 (TCN). 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 endo-proteolytic 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 intra-membranous cleavage of APP occurs.

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Author notes

  1. Peter T. Lansbury and Kenneth S. Kosik: Correspondence should be addressed to K.S.K. email: Kosik@cnd.bwh.harvard.edu or P.T.L. email: lansbury@cnd.bwh.harvard.edu

  2. Seung-Jae Lee and Udaya Liyanage: S.-J.L and U.L. contributed equally to this work

Authors and Affiliations

  1. Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM, Boston, Massachusetts, 02115

    Seung-Jae Lee, Udaya Liyanage, Weiming Xia, Peter T. Lansbury Jr. & Kenneth S. Kosik

  2. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, 02142

    Perry E. Bickel

  3. Department of Medicine, Diabetes Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114

    Perry E. Bickel

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Lee, SJ., Liyanage, U., Bickel, P. et al. A detergent-insoluble membrance compartment contains Aβ in vivo. Nat Med 4, 730–734 (1998). https://doi.org/10.1038/nm0698-730

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