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 A Disintegrin and Metalloproteinase with Thrombospondin motifs 1 (ADAMTS1) has been further suggested in 2021 and 2022. To verify the association, we re-sequenced ADAMTS1 of clinical AD samples and subsequently identified a novel rare variant c.–2067A > C with watchable relevance (whereas the P-value was not significant after adjustment). Dual-luciferase assay showed that the variant sharply stimulated ADAMTS1 expression. In addition, ADAMTS1 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 in vitro and in vivo. 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 ADAMTS1, and thus spatial cognition was restored as well. This study revealed the contribution of ADAMTS1 to the connection of genetic and acquired factors with APP metabolism, and its potential in reducing hippocampal amyloid and consequent risk of AD.

Cyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma

“…For example, L1CAM-FL was cleaved by ADAM10 to generate a soluble 180-kDa L1CAM (L1-180) [ 24 ]. ADAMTS1 and ADAM10 belong to the ADAM family and have both disintegrin and zinc metalloprotease domains, which implies that they might have functions related to the ECM and adhesion molecules by a similar approach [ 25 ]. Herein, we observed that overexpression and knockdown of ADAMTS1 respectively promoted and suppressed expression of L1-180 in HSC-3 and HSC-3M cells (Fig.…”

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

“…The gene’s protein product has been suggested as a marker protein for neurodegeneration, 102 and hippocampal amyloid-β load was alleviated after introducing ADAMTS1 in a mouse model of AD. 103 Considering that five of six predicted AD-risk target genes were significantly differentially expressed in inhibitory neurons, it is plausible that altered glia-neuron communication affects inhibitory neurons more severely than excitatory neurons in the 12-month 3xTg-AD hippocampus. Four ligand-receptor pairs with AD risk genes also included an AD risk gene as a ligand ( Calm2 ) or receptor ( App ) of interactions originating from microglia.…”

Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease

“…Both are involved in extracellular matrix damage and repair. 36 ADAMTS1 is thought to be involved in hydrolysis of APP and consequently decreases Aβ generation through inhibiting β-secretase-mediated cleavage. Clinically the gene may also affect cognitive ability by its effect on hippocampal amyloid processing.…”