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Abnormal and deficient processing of beta-amyloid precursor protein in familial Alzheimer's disease lymphoblastoid
1Department of Radiation Biophysics, Kobe University School of Medicine, Japan.
Abstract:
Western blot analysis showed abnormal processing of beta-amyloid precursor protein (APP) in lymphoblastoid cell lines (LCLs) of familial Alzheimer's disease (FAD). Antibody raised against central APP751 revealed that media of early and late-onset FAD LCLs had highly increased amounts of a 120 kD long-lived. SDS-stable, heat-labile complex of the Kunitz protease inhibitor domain of secreted APP and a approximately 70 kD FAD-specific, yet unidentified serine protease. Antibody against the beta A4-cytoplasmic domain showed a slower APP processing and increased amounts of 16 kD C-terminal preamyloid in lysates of early and late-onset FAD LCLs, first indicating a deficient intra-beta A4 proteolysis in FAD as a possible cause of abundant amyloid deposits in AD brain.
Insights
Familial Alzheimer's disease (FAD) shows abnormal processing of beta-amyloid precursor protein (APP). This study indicates deficient intra-beta A4 proteolysis in FAD, potentially causing amyloid deposits in Alzheimer's disease (AD) brains.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) is characterized by amyloid deposits.
- Familial Alzheimer's disease (FAD) presents with abnormal processing of beta-amyloid precursor protein (APP).
Purpose of the Study:
- To investigate the molecular mechanisms underlying APP processing abnormalities in FAD.
- To identify potential causes for increased amyloid deposition in FAD.
Main Methods:
- Western blot analysis of lymphoblastoid cell lines (LCLs) from FAD patients.
- Antibody-based detection of APP and its processing products.
- Characterization of protein complexes in FAD LCL media and lysates.
Main Results:
- Increased amounts of a 120 kD complex involving secreted APP's Kunitz protease inhibitor domain and an unidentified serine protease were found in FAD LCL media.
- Slower APP processing and elevated levels of 16 kD C-terminal preamyloid were observed in FAD LCL lysates.
- Evidence suggests a deficiency in intra-beta A4 proteolysis in FAD.
Conclusions:
- Deficient intra-beta A4 proteolysis in FAD may lead to the accumulation of amyloid deposits in AD brains.
- Identified a novel FAD-specific serine protease involved in APP processing.
- Highlights potential therapeutic targets for FAD by addressing APP processing defects.