A DETERGENT-INSOLUBLE MEMBRANE COMPARTMENT CONTAINS A-BETA IN-VIVO

Ordered assembly of the amyloid-beta protein (A beta) into amyloid fib rils is a critical step in Alzheimer's disease (AD). To release the am yloidogenic peptide A beta from the Alzheimer amyloid precursor protei n (APP), two secretases act sequentially: first, beta-secretase cleave s close to the membrane within the ectodomain and then gamma-secretase cuts within the transmembrane domain(1). 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 el evated; thus, the secretory pathway may be unaffected, and factors oth er than the extracellular concentration of A beta may contribute to th e aggregation properties of the peptide. A beta is also present in int racellular compartments(2-5). The two gamma-secretase cleavage product s, A beta 42 and A beta 40, were found in different compartments: A be ta 42 in the endoplasmic reticulum (ER)/intermediate compartment(3-5), and A beta 40 in the trans-Golgi network(2,4) (TGN). The cellular com partments that harbor A beta are target sites for therapeutic interven tion. Here we report that in the brain, the principal compartment in w hich A beta resides is a detergent-insoluble glycolipid-enriched membr ane domain (DIG). Also present in the DIC fractions are the endoproteo lytic fragments of presenilin-1 (PS1) and APP. The presence of these p roteins, which all contribute to the generation of A beta, indicates t hat the DIG fraction is probably where the intramembranous cleavage of APP occurs.