A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing.
Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the gamma-secretase site. This was termed -cleavage. Brefeldin A treatment and pulse-chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of -cleavage is decreased by expression of presenilin-1 mutants known to impair Abeta formation, and it is sensitive to the gamma-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.
Weidemann
Andreas
A
Zentrum für Molekulare Biologie Heidelberg, INF 282, 69120 Heidelberg, Germany.
Eggert
Simone
S
Reinhard
Friedrich B M
FB
Vogel
Markus
M
Paliga
Krzysztof
K
Baier
Gottfried
G
Masters
Colin L
CL
Beyreuther
Konrad
K
Evin
Geneviève
G
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D017931:DNA Primers; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D053764:Presenilin-1; D011480:Protease Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D008565:Membrane Proteins; D053764:Presenilin-1; D011480:Protease Inhibitors