Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Proteolytic processing of Alzheimer's disease associated proteins

J Neural Transm Suppl 53: 159-67

Authors/Editors: Haass C
Grunberg J
Capell A
Wild-Bode C
Leimer U
Walter J
Yamazaki T
Ihara I
Zweckbronner I
Jakubek C
Baumeister R
Publication Date: 1998
Type of Publication: Review
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.

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