Induction of A Disintegrin and Metalloproteinase with Thrombospondin motifs 1 by a rare variant or cognitive activities reduces hippocampal amyloid-β and consequent Alzheimer’s disease risk

Abstract

Amyloid-β (Aβ) derived from amyloid precursor protein (APP) hydrolysis is acknowledged as the predominant hallmark of Alzheimer's disease (AD) that especially correlates to genetics and daily activities. In 2019, meta-analysis of AD has discovered five new risk loci among which <i>A Disintegrin and Metalloproteinase with Thrombospondin motifs 1</i> (<i>ADAMTS1</i>) has been further suggested in 2021 and 2022. To verify the association, we re-sequenced <i>ADAMTS1</i> of clinical AD samples and subsequently identified a novel rare variant c.-2067A > C with watchable relevance (whereas the <i>P</i>-value was not significant after adjustment). Dual-luciferase assay showed that the variant sharply stimulated <i>ADAMTS1</i> expression. In addition, <i>ADAMTS1</i> was also clearly induced by pentylenetetrazol-ignited neuronal activity and enriched environment (EE). Inspired by the above findings, we investigated ADAMTS1's role in APP metabolism <i>in vitro</i> and <i>in vivo</i>. Results showed that ADAMTS1 participated in APP hydrolysis and consequently decreased Aβ generation through inhibiting β-secretase-mediated cleavage. In addition, we also verified that the hippocampal amyloid load of AD mouse model was alleviated by the introduction of <i>ADAMTS1</i>, and thus spatial cognition was restored as well. This study revealed the contribution of <i>ADAMTS1</i> to the connection of genetic and acquired factors with APP metabolism, and its potential in reducing hippocampal amyloid and consequent risk of AD.