Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity.

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Emerging evidence implicates neutrophils in Alzheimer's disease (AD) pathogenesis.
• Neutrophil granule proteins, including cationic antimicrobial protein of 37 kDa (CAP37), cathepsin G (CG), and neutrophil elastase (NE), bind and can cleave amyloid-beta peptide Aβ₁-42, a key player in AD.

Purpose of the Study:

• To compare the effects of CAP37, CG, and NE on Aβ₁-42 fibrillation and neurotoxicity.
• To investigate the mechanisms by which these neutrophil proteins modulate Aβ₁-42 aggregation and associated neuronal damage.

Main Methods:

• Utilized mass spectrometry and in vitro aggregation assays to analyze Aβ₁-42 fibrillation.
• Assessed the neurotoxicity of Aβ₁-42 aggregates in cultured neurons.
• Investigated the effects of full-length proteins and a CAP37-derived peptide.

Main Results:

• NE and CG efficiently cleaved Aβ₁-42, inhibiting its aggregation and neutralizing neurotoxicity.
• CAP37 inhibited Aβ₁-42 aggregation via a quenching effect but did not neutralize neurotoxicity.
• A peptide derived from CAP37 mimicked the aggregation inhibition and also neutralized Aβ₁-42 neurotoxicity.

Conclusions:

• Neutrophil granule proteins exhibit distinct mechanisms in modulating Aβ₁-42 aggregation and neurotoxicity.
• A CAP37-derived peptide shows promise in inhibiting both Aβ₁-42 aggregation and its downstream neurotoxic effects.
• These findings suggest a potential therapeutic strategy for developing novel disease-modifying drugs for Alzheimer's disease.