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Proteolytic processing of Alzheimer's disease associated proteins
C Haass1, J Grünberg, A Capell
1Central Institute for Mental Health, Department of Molecular Biology, Mannheim, Federal Republic of Germany.
Abstract:
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.
Insights
Presenilin (PS) proteins are crucial in Alzheimer's disease (AD) pathology, influencing amyloid beta-peptide (A beta) generation. Mutations in PS genes disrupt A beta 42 production and interfere with NOTCH signaling, impacting familial AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyloid beta-peptide (A beta) accumulation in senile plaques is central to Alzheimer's disease (AD) pathology.
- Mutations in beta-amyloid precursor protein (beta APP) and presenilin (PS) genes are linked to early-onset familial AD (FAD).
- Presenilin proteins are implicated in the abnormal generation of A beta 42, a key pathogenic species.
Purpose of the Study:
- To investigate the role of presenilin proteins in A beta generation and Alzheimer's disease.
- To explore the cellular localization and processing of presenilin proteins.
- To examine the involvement of presenilin proteins in NOTCH signaling and its relation to FAD.
Main Methods:
- Analysis of A beta generation in relation to beta APP and PS mutations.
- Characterization of presenilin protein processing, including N-terminal fragments (NTF) and C-terminal fragments (CTF).
- Localization studies of presenilin proteins within cellular compartments like the endoplasmic reticulum (ER) and Golgi.
- Utilizing Caenorhabditis elegans as a model organism to study presenilin function in NOTCH signaling.
Main Results:
- Presenilin mutations lead to abnormal generation of A beta 42, supporting its role in AD.
- Presenilin proteins are processed into NTF and CTF, and can be further cleaved by caspases.
- Presenilin proteins are localized in the ER and early Golgi, compartments involved in A beta 42 generation.
- Presenilin proteins are involved in NOTCH signaling, and FAD-causing mutations disrupt this function.
Conclusions:
- Presenilin proteins play a critical role in both A beta generation and NOTCH signaling, linking these pathways in Alzheimer's disease.
- The localization of presenilin proteins in the ER and Golgi is significant for A beta 42 production.
- Understanding presenilin's dual role offers insights into therapeutic strategies for familial Alzheimer's disease.