A detergent-insoluble membrane compartment contains A beta in vivo

Nat Med. 1998 Jun;4(6):730-4. doi: 10.1038/nm0698-730.


Ordered assembly of the amyloid-beta protein (A beta) into amyloid fibrils is a critical step in Alzheimer's disease (AD). To release the amyloidogenic peptide A beta from the Alzheimer amyloid precursor protein (APP), two secretases act sequentially: first, beta-secretase cleaves close to the membrane within the ectodomain and then gamma-secretase cuts within the transmembrane domain. The sites of gamma-secretase cleavage are after residues 40 or 42 of A beta. Except in those rare cases of AD caused by a mutation, levels of secreted A beta are not elevated; thus, the secretory pathway may be unaffected, and factors other than the extracellular concentration of A beta may contribute to the aggregation properties of the peptide. A beta is also present in intracellular compartments. The two gamma-secretase cleavage products, A beta42 and A beta40, were found in different compartments: A beta42 in the endoplasmic reticulum (ER)/intermediate compartment, and A beta40 in the trans-Golgi network (TGN). The cellular compartments that harbor A beta are target sites for therapeutic intervention. Here we report that in the brain, the principal compartment in which A beta 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 A beta, indicates that the DIG fraction is probably where the intramembranous cleavage of APP occurs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / metabolism
  • Brain Chemistry
  • CHO Cells
  • Caveolin 1
  • Caveolins*
  • Cell Compartmentation*
  • Cell Membrane / chemistry*
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Cholesterol / metabolism
  • Cricetinae
  • Detergents
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / metabolism
  • Glycolipids / metabolism
  • Golgi Apparatus / chemistry
  • Golgi Apparatus / metabolism
  • Membrane Proteins / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Subcellular Fractions / chemistry
  • Subcellular Fractions / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Caveolin 1
  • Caveolins
  • Detergents
  • Glycolipids
  • Membrane Proteins
  • flotillins
  • Cholesterol