Proteolytic processing of Alzheimer's disease associated proteins.
Amyloid beta-peptide (A beta), the major component of senile plaques, is generated by proteolytic processing from the beta-amyloid precursor protein (beta APP). Mutations within the beta APP gene cause early onset familial AD (FAD) by affecting A beta generation. Interestingly, the much more abundant mutations within the presenilin (PS) genes also result in the abnormal generation of a 42 residue A beta (A beta 42), thus clearly supporting a pivotal role of A beta for the pathology of AD. PS proteins are proteolytically processed into stable 30 kDa N-terminal fragments (NTF) and 20 kDa C-terminal fragments (CTF). Beside the conventional proteolytic pathway. PS proteins can also be cleaved further C-terminal by proteases of the caspase superfamily. PS proteins were localized within the endoplasmic reticulum (ER) and early Golgi, compartments which we have demonstrated to be involved in A beta 42 generation and intracellular accumulation. Using Caenorhabditis elegans as a simple animal model, we demonstrate that PS proteins are involved in NOTCH signaling FAD causing mutations interfere with the biological function of PS proteins in NOTCH signaling.
Haass
C
C
Central Institute for Mental Health, Department of Molecular Biology, Mannheim, Federal Republic of Germany.
Grünberg
J
J
Capell
A
A
Wild-Bode
C
C
Leimer
U
U
Walter
J
J
Yamazaki
T
T
Ihara
I
I
Zweckbronner
I
I
Jakubek
C
C
Baumeister
R
R
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D010450:Endopeptidases