A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor

Area of Science:

• Neuroscience
• Molecular Biology
• Pathogenesis of Alzheimer Disease

Background:

• Amyloid beta-protein precursor (AβPP) fragments are central to Alzheimer disease (AD) pathogenesis.
• AβPP generates amyloid beta-protein, a key component of senile plaques.
• The role of AβPP proteolytic processing in AD neuronal death is under investigation.

Purpose of the Study:

• To investigate the proteolytic cleavage of AβPP by caspases.
• To identify novel peptides generated from AβPP cleavage.
• To determine the potential role of these peptides and caspase activity in Alzheimer disease.

Main Methods:

• Proteolytic cleavage assays using caspases.
• Peptide identification and characterization.
• Immunohistochemical analysis of human brain tissue from AD patients and controls.

Main Results:

• Caspase cleavage of AβPP at the C terminus generates a novel peptide, C31.
• The C31 peptide is a potent inducer of apoptosis (programmed cell death).
• Caspase-cleaved AβPP and activated caspase-9 were detected in Alzheimer disease brains but not in controls.

Conclusions:

• Caspase-mediated cleavage of AβPP produces the cytotoxic C31 peptide.
• The presence of caspase-cleaved AβPP and activated caspase-9 in AD brains suggests their involvement.
• This pathway may contribute to the characteristic neuronal death observed in Alzheimer disease.