Proteolytic processing of Alzheimer's disease associated proteins

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.