| Property | Value | [@lemarchant2013] |----------|-------| [@rodrigues2019] | Gene Symbol | ADAMTS4 | [@bhagavathi2023] | Full Name | ADAM Metallopeptidase with Thrombospondin Type 1 Motif 4 | [@hamel2008] | Aliases | Aggrecanase-1, ADMP-1 | | Chromosomal Location | 1q23.3 | | NCBI Gene ID | [9507](https://www.ncbi.nlm.nih.gov/gene/9507) | | OMIM ID | [603282](https://omim.org/entry/603282) | | Ensembl ID | [ENSG00000158859](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158859) | | UniProt ID | [O75173](https://www.uniprot.org/uniprot/O75173) | | Encoded Protein | [ADAMTS-4 protein](/proteins/adamts4-protein) | | Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), osteoarthritis, spinal cord injury |
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Overview
ADAMTS4 is a human gene whose product aDAMTS4** encodes a member of the ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin motifs) family of secreted zinc metalloproteinases. ADAMTS-4, also known as aggrecanase-1, is a multidomain extracellular protease with broad substrate specificity that plays important roles in both the peripheral and central nervous system. Variants in ADAMTS4 have been implicated in Alzheimer's Disease (AD), Osteoarthritis, Spinal Cord Injury and CNS Repair. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Function
ADAMTS4 encodes a member of the ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin motifs) family of secreted zinc metalloproteinases. ADAMTS-4, also known as aggrecanase-1, is a multidomain extracellular protease with broad substrate specificity that plays important roles in both the peripheral and central nervous system.
Key normal physiological functions include:
Extracellular matrix (ECM) remodeling — ADAMTS-4 cleaves aggrecan and other proteoglycans (versican, brevican, neurocan) in the ECM, facilitating tissue remodeling during development and repair
Perineuronal net (PNN) degradation — Cleaves brevican and other chondroitin sulfate proteoglycans (CSPGs) that form PNNs, structures critical for synaptic stability and [neural plasticity](/mechanisms/synaptic-plasticity)
Amyloid-beta clearance — Identified as an [amyloid-beta (Aβ)](/proteins/amyloid-beta)-degrading enzyme that can cleave Aβ peptides, potentially contributing to amyloid homeostasis in the brain
Neuroinflammatory modulation — Expression is upregulated in reactive [astrocytes](/cell-types/astrocytes) and [microglia](/cell-types/microglia) during neuroinflammation
Spinal cord plasticity — Promotes axonal regeneration and plasticity after spinal cord injury by degrading inhibitory CSPGs
Disease Associations
Alzheimer's Disease (AD)
ADAMTS4 has emerged as a significant gene in [Alzheimer's disease](/diseases/alzheimers-disease) through multiple lines of evidence:
Genome-wide association studies (GWAS) — A missense variant in ADAMTS4 (rs4575098, p.Ile72Val) was identified as a protective factor against AD in a large-scale GWAS meta-analysis of over 94,000 individuals. Carriers of the rare allele showed significantly reduced AD risk (OR ≈ 0.88)
Amyloid-beta degradation — ADAMTS-4 cleaves Aβ at multiple sites within the peptide, representing a novel Aβ-degrading pathway complementary to [neprilysin](/proteins/neprilysin) and [insulin-degrading enzyme](/entities/insulin-degrading-enzyme)
Protective variant mechanism — The protective I72V variant increases ADAMTS-4 enzymatic activity, enhancing Aβ clearance and reducing amyloid plaque burden in mouse models
Perineuronal net disruption — Dysregulated ADAMTS-4 activity in AD may contribute to PNN breakdown, destabilizing synaptic connections and accelerating [tau](/proteins/tau) pathology spread
Reactive astrocyte expression — ADAMTS4 is highly upregulated in disease-associated [astrocytes](/entities/astrocytes) surrounding amyloid plaques, suggesting a role in the glial response to Aβ deposition
Osteoarthritis
ADAMTS4 plays a well-established role in osteoarthritis through:
Degradation of aggrecan in articular cartilage, leading to cartilage destruction
Upregulation by pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)
Therapeutic target: ADAMTS-4 inhibitors are under investigation for cartilage protection
Spinal Cord Injury and CNS Repair
ADAMTS-4-mediated degradation of inhibitory CSPGs promotes axonal regeneration after CNS injury
Therapeutic delivery of ADAMTS-4 enhances functional recovery in spinal cord injury models
Involved in Wallerian degeneration and nerve remodeling
Expression
ADAMTS4 shows regulated expression across brain regions:
High expression: Cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus) (particularly CA1 and dentate gyrus), striatum
Cellular expression: Primarily [astrocytes](/cell-types/astrocytes), with lower expression in [neurons](/cell-types/neurons) and [oligodendrocytes](/cell-types/oligodendrocytes)
Disease-state upregulation: Dramatically increased in reactive astrocytes near amyloid plaques in AD brain tissue
Subcellular localization: Secreted enzyme; localized to the extracellular space and cell surface
[Jansen et al., Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk (2019) (2019)](https://doi.org/10.1038/s41588-018-0311-9)
[Jonsson et al., Variant of TREM2 associated with the risk of Alzheimer's disease (2013) (2013)](https://doi.org/10.1056/NEJMoa1211103)
[Tortorella et al., Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins (1999) (1999)](https://doi.org/10.1126/science.284.5420.1664)
[Lemarchant et al., ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis (2016) (2016)](https://doi.org/10.1186/s13024-016-0078-3)
[Lemarchant et al., ADAMTS proteoglycanases in the physiological and pathological central nervous system (2013) (2013)](https://doi.org/10.1111/jnc.12)
[Rodrigues et al., ADAMTS4 variant associated with Alzheimer's disease risk reduces amyloid-β levels (2019) (2019)](https://doi.org/10.1016/j.jalz.2019.06.4950)
[Unknown, Bhagavathi Bhavya & Bhowmik, Decoding the role of ADAMTS4 in Alzheimer's disease: a computational approach (2023) (2023)](https://doi.org/10.1016/j.ijbiomac.2023.126862)
[Hamel et al., De novo variants in ADAMTS4 are associated with arthrogryposis and neurological features (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/29847634/)
Pathway Diagram
The following diagram shows the key molecular relationships involving ADAMTS4 Gene discovered through SciDEX knowledge graph analysis: