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Potential beta PP-processing proteinase activities from Alzheimer's and control brain tissues
U S Ladror1, G T Wang, W L Klein
1Abbott Laboratories, Abbott Park, Illinois 60064.
Journal of Protein Chemistry
|May 1, 1994
Summary
Alzheimer
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder.
- Amyloid-beta precursor protein (APP) processing is central to AD pathogenesis.
- Proteolytic enzymes play a critical role in APP cleavage.
Purpose of the Study:
- To investigate alterations in proteinase activities in Alzheimer's disease (AD) brains.
- To analyze cleavage site specificities of enzymes acting on amyloid-beta precursor protein (APP).
- To compare enzyme activities between control and AD brain extracts.
Main Methods:
- Utilized fluorogenic peptide substrates mimicking APP secretory and amyloidogenic cleavage sites.
- Assessed endopeptidase and carboxypeptidase activities in human brain extracts.
- Determined optimal pH for enzyme activities and compared profiles between control and AD brains.
Main Results:
- Identified distinct cleavage patterns for APP in control versus AD brains.
- Observed altered cleavage site preference near the amyloidogenic site in AD brains.
- Found reduced overall proteolytic activity in AD brains, particularly at neutral to alkaline pH.
- Detected increased proteolytic activity at acidic pH in AD brains compared to controls.
Conclusions:
- Proteolytic enzyme levels and activities are significantly altered in Alzheimer's disease brains.
- Specific changes in APP cleavage site utilization suggest dysregulation of secretase activities in AD.
- The pH-dependent activity profiles highlight complex proteolytic alterations in the AD brain environment.