Identification of ADAMTS5 as APP-Cleaving Enzyme at the APP669 Site

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Cerebral amyloid-beta (Aβ) deposition is a hallmark of early Alzheimer's disease (AD).
• APP669-711 is a novel plasma peptide and a potential biomarker for cerebral Aβ burden.
• ADAMTS4 was previously identified as a key enzyme in APP669-711 production.

Purpose of the Study:

• To identify the enzymes responsible for the remaining 60% of APP669-site cleavage.
• To investigate the role of ADAMTS5 in APP669-711 production in vitro and in vivo.
• To explore the potential contribution of ADAMTS5 to plasma APP669-711 in AD patients.

Main Methods:

• In vitro enzymatic assays to compare APP669-site cleavage activity of ADAMTS4 and ADAMTS5.
• Analysis of the role of the spacer (Sp) domain in regulating protease activity.
• In vivo experiments to assess plasma APP669-711 production under healthy conditions.

Main Results:

• ADAMTS5 exhibits stronger APP669-site cleavage activity in vitro compared to ADAMTS4.
• The spacer domain of ADAMTS5/ADAMTS4 regulates their differential cleavage activity.
• In vivo studies did not confirm a role for ADAMTS5 in plasma APP669-711 production in healthy individuals.

Conclusions:

• ADAMTS5 is a potent APP669-cleaving enzyme, with activity regulated by its spacer domain.
• ADAMTS5 may contribute to plasma APP669-711 production in Alzheimer's disease patients, particularly those with comorbid conditions.
• Further research is warranted to elucidate the in vivo significance of ADAMTS5 in AD pathogenesis.