ADAM10 — A Disintegrin And Metalloproteinase Domain 10

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ADAM10 — A Disintegrin And Metalloproteinase Domain 10

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ADAM10 — A Disintegrin And Metalloproteinase Domain 10

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">adam10</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ADAM10</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>A Disintegrin And Metalloproteinase Domain 10</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>15q21.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>102</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000137845</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O14672</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>602192</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>748 amino acids</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Function</td>
</tr>
<tr>
<td class="label">APP (Amyloid Precursor Protein)</td>
<td>Non-amyloidogenic cleavage → sAPPα</td>
</tr>
<tr>
<td class="label">Notch receptors</td>
<td>Signaling, neurodevelopment</td>
</tr>
<tr>
<td class="label">N-cadherin</td>
<td>Cell adhesion, synaptic plasticity</td>
</tr>
<tr>
<td class="label">E-cadherin</td>
<td>Cell-cell adhesion</td>
</tr>
<tr>
<td class="label">EphA receptors</td>
<td>Axon guidance, synaptogenesis</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Microglial activation</td>
</tr>
<tr>
<td class="label">Prion protein (PrP)</td>
<td>Cellular homeostasis</td>
</tr>

...

ADAM10 — A Disintegrin And Metalloproteinase Domain 10

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">adam10</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ADAM10</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>A Disintegrin And Metalloproteinase Domain 10</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>15q21.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>102</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000137845</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O14672</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>602192</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>748 amino acids</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Function</td>
</tr>
<tr>
<td class="label">APP (Amyloid Precursor Protein)</td>
<td>Non-amyloidogenic cleavage → sAPPα</td>
</tr>
<tr>
<td class="label">Notch receptors</td>
<td>Signaling, neurodevelopment</td>
</tr>
<tr>
<td class="label">N-cadherin</td>
<td>Cell adhesion, synaptic plasticity</td>
</tr>
<tr>
<td class="label">E-cadherin</td>
<td>Cell-cell adhesion</td>
</tr>
<tr>
<td class="label">EphA receptors</td>
<td>Axon guidance, synaptogenesis</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Microglial activation</td>
</tr>
<tr>
<td class="label">Prion protein (PrP)</td>
<td>Cellular homeostasis</td>
</tr>
<tr>
<td class="label">IL-6R</td>
<td>Inflammation</td>
</tr>
<tr>
<td class="label">TNF-α</td>
<td>Pro-inflammatory cytokine</td>
</tr>
<tr>
<td class="label">Mutation</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">p.Q170H</td>
<td>>70% reduced α-secretase activity; 1.5-3.5x elevated Aβ</td>
</tr>
<tr>
<td class="label">p.R181G</td>
<td>Similar reduction in activity; elevated Aβ</td>
</tr>
<tr>
<td class="label">p.Tyr167*</td>
<td>Truncated non-functional protein</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Retinoids (Acitretin)</td>
<td>Transcriptional upregulation</td>
</tr>
<tr>
<td class="label">PPARγ agonists</td>
<td>Increase ADAM10 expression</td>
</tr>
<tr>
<td class="label">LXR/RXR agonists</td>
<td>Transcriptional activation</td>
</tr>
<tr>
<td class="label">HDAC inhibitors</td>
<td>Epigenetic derepression</td>
</tr>
<tr>
<td class="label">Etazolate (EHT 0202)</td>
<td>Direct activation</td>
</tr>
<tr>
<td class="label">BACE1 inhibition</td>
<td>Indirectly favor α-cleavage</td>
</tr>
<tr>
<td class="label">Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Cerebral cortex</td>
<td>High</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>High</td>
</tr>
<tr>
<td class="label">Thalamus</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Basal ganglia</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Substantia nigra</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">Notch signaling</td>
<td>ADAM10 is primary Notch sheddase</td>
</tr>
<tr>
<td class="label">Wnt/β-catenin</td>
<td>Cross-talk in neuroprotection</td>
</tr>
<tr>
<td class="label">MAPK/ERK</td>
<td>Activity-regulated ADAM10</td>
</tr>
<tr>
<td class="label">PKC</td>
<td>Phosphorylation modulates activity</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Description</td>
</tr>
<tr>
<td class="label">ADAM10 knockout mice</td>
<td>Complete loss of ADAM10</td>
</tr>
<tr>
<td class="label">Conditional neuronal KO</td>
<td>Neuron-specific deletion</td>
</tr>
<tr>
<td class="label">ADAM10 overexpressing mice</td>
<td>Neuronal overexpression</td>
</tr>
<tr>
<td class="label">Q170H knock-in</td>
<td>Patient mutation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">Alzheimer's Disease</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">104 edges</a></td>
</tr>
</table>

Introduction

ADAM10 (A Disintegrin And Metalloproteinase Domain-Containing Protein 10) is a gene located on chromosome 15q21.3 that encodes the principal α-secretase responsible for the non-amyloidogenic cleavage of the [Amyloid Precursor Protein (APP)](/[/proteins/app]). By cleaving APP within the [amyloid-beta](/proteins/amyloid-beta) domain, ADAM10 precludes the generation of toxic amyloid-beta peptides, making it a key protective factor against Alzheimer's Disease (AD) [@potential2009][@adam2014].

ADAM10 is a member of the ADAM (A Disintegrin And Metalloproteinase) family of transmembrane proteins, which play important roles in cell adhesion, proteolysis, and signaling. As the constitutive α-secretase in neurons, ADAM10 is essential for maintaining the balance between amyloidogenic and non-amyloidogenic APP processing—a balance that is central to the amyloid hypothesis of AD pathogenesis.

Loss-of-function mutations in ADAM10 have been identified in families with both late-onset and early-onset Alzheimer's Disease, establishing it as a bona fide AD susceptibility gene [@secretase2020]. The therapeutic potential of ADAM10 modulation has been extensively investigated, as enhancing ADAM10 activity could simultaneously reduce toxic Aβ production and increase neuroprotective sAPPα levels [@therapeutic2023].

Gene Information

Protein Structure and Function

Domain Architecture

ADAM10 is synthesized as a 748-amino-acid zymogen with the following domain structure [@saftig2009]:

Prodomain (residues 1-214): Functions as an intramolecular chaperone for proper folding; removed by furin/proprotein convertases during maturation. AD mutations Q170H and R181G reside in this domain [@adam2014].

Metalloproteinase domain (residues 215-467): Contains the catalytic zinc-binding motif HEXXHXXGXXH that mediates substrate cleavage. The catalytic zinc ion (Zn²⁺) is essential for proteolytic activity.

Disintegrin domain (residues 468-535): Participates in substrate recognition and cell-cell interactions. Contains an RGD sequence motif that can mediate integrin binding.

Cysteine-rich domain (residues 536-654): Mediates protein-protein interactions and contributes to substrate specificity.

Transmembrane domain (residues 655-677): Single-pass membrane anchor (type I membrane protein).

Cytoplasmic tail (residues 678-748): Contains regulatory motifs including a PDZ-binding motif and serine/threonine phosphorylation sites that regulate trafficking and activity.

Catalytic Mechanism

The metalloproteinase domain contains the HExxHxxGxxH zinc-binding motif coordinated to a catalytic zinc ion. The mechanism involves:

Zinc-bound water molecule: Acts as the nucleophile

Glu²⁴² (general base): Activates the water molecule

His²¹⁵/His²¹⁹/His²²⁵ (catalytic triad): Coordinate zinc ion

Met²³⁶ (Met-turn): Provides structural support

Substrate Specificity

ADAM10 is a promiscuous "sheddase" that cleaves the ectodomains of numerous transmembrane proteins [@deuss2018]:

Normal Physiological Functions

Non-Amyloidogenic APP Processing

ADAM10 cleaves APP between residues Lys⁶⁸⁷ and Leu⁶⁸⁸ (within the Aβ sequence), generating:

Soluble APPα (sAPPα): Released into the extracellular space
C-terminal fragment α (CTFα/C83): Membrane-bound fragment

This cleavage precludes Aβ generation because it cuts within the Aβ peptide domain [@postina2001][@zurhove2008].

sAPPα Functions

The released sAPPα ectodomain has multiple neuroprotective properties:

Neurotrophic effects: Promotes neuronal survival and differentiation

Synaptic plasticity: Enhances LTP and memory formation

Anti-inflammatory: Modulates microglial activation

Anti-oxidant: Reduces oxidative stress

Neurogenesis: Stimulates neural stem cell proliferation

Competition with BACE1

ADAM10 and BACE1 (β-secretase) compete for APP substrate at the cell surface and in endosomes [@seyfried2010]. The relative activity of these two enzymes determines the balance between:

Non-amyloidogenic pathway: ADAM10 → sAPPα + C83 (protective)
Amyloidogenic pathway: BACE1 → sβAPP + C99 → Aβ (toxic)

This balance is central to AD pathogenesis.

Notch Signaling

ADAM10 is required for Notch receptor activation through proteolytic cleavage [@saftig2009]:

Initial cleavage by ADAM10 (extracellular domain shedding)

γ-secretase cleavage (intramembrane)

This pathway is essential for:

Neurodevelopment
Cell fate determination
Synaptic plasticity

Disease Associations

Alzheimer's Disease

ADAM10 mutations are linked to Alzheimer's Disease through loss of α-secretase function:

Key Mutations

Prodomain Missense Mutations (Late-Onset AD):

Mechanism: These missense mutations impair the intramolecular chaperone function of the ADAM10 prodomain, leading to:

Improper enzyme folding
Reduced maturation
Decreased surface expression
Diminished catalytic activity

In Vivo Evidence: In Tg2576 AD transgenic mice, both Q170H and R181G mutations attenuated ADAM10 α-secretase activity, shifted APP processing toward β-secretase-mediated cleavage, and enhanced Aβ plaque burden and reactive gliosis [@adam2014].

Therapeutic Implications

ADAM10 is a prime therapeutic target for AD because enhancing its activity could simultaneously:

Reduce toxic Aβ production

Increase neuroprotective sAPPα levels

Strategies to Enhance ADAM10 Activity

Challenges

ADAM10 has numerous substrates beyond APP, raising concerns about off-target effects (particularly Notch-related toxicity)
Achieving CNS-specific ADAM10 modulation remains technically challenging
No ADAM10-based therapy has yet reached phase III clinical trials for AD

Expression Patterns

Brain Expression

ADAM10 is widely expressed in the central nervous system:

Cellular Localization

Neuronal membrane: Primary location for APP cleavage
Endosomes: Active site of APP processing
Synaptic vesicles: Regulated release of sAPPα

Regulation

ADAM10 activity is regulated at multiple levels [@endres2017]:

Transcription: Influenced by retinoic acid, cytokines, and neuronal activity

Prodomain processing: Furin-mediated activation

Trafficking: RAB GTPases regulate movement to membrane

Post-translational modification: Phosphorylation affects activity

Molecular Pathways

APP Processing Pathway

APP (transmembrane)
↓
├─→ ADAM10 (α-secretase) → sAPPα + C83 (non-amyloidogenic)
│
└─→ BACE1 (β-secretase) → sβAPP + C99 → γ-secretase → Aβ (amyloidogenic)

Signaling Interactions

Animal Models

Key Publications

[Kim M, et al. (2009) Potential late-onset AD-associated mutations in ADAM10 attenuate alpha-secretase activity. Hum Mol Genet 18:3987-3996](https://pubmed.ncbi.nlm.nih.gov/19181795/)

[Lammich S, et al. (2014) ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation. Neuron 83:1204-1217](https://pubmed.ncbi.nlm.nih.gov/25002037/)

[Peters F, et al. (2020) α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial AD. Acta Neuropathol Commun 8:160](https://pubmed.ncbi.nlm.nih.gov/33293482/)

[Tang BL, et al. (2023) Therapeutic potential of ADAM10 modulation in AD. Cell Mol Biol Lett 28:44](https://pubmed.ncbi.nlm.nih.gov/37620554/)

[Endres K, Deller T. (2017) Regulation of ADAM10 in vitro and in vivo. Front Mol Neurosci 10:56](https://pubmed.ncbi.nlm.nih.gov/28769790/)

[Kuhn PH, et al. (2010) ADAM10 is the physiologically relevant α-secretase in neurons. EMBO J 29:1617-1629](https://pubmed.ncbi.nlm.nih.gov/20852586/)

External Links

[NCBI Gene: ADAM10](https://www.ncbi.nlm.nih.gov/gene/102)
[UniProt: O14672](https://www.uniprot.org/uniprot/O14672)
[Ensembl: ENSG00000137845](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137845)
[Allen Human Brain Atlas: ADAM10](https://human.brain-map.org/microarray/search/show?search_term=ADAM10)
[OMIM: 602192](https://omim.org/entry/602192)

References

[Kim M, et al. (2009) Potential late-onset Alzheimer's Disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity. Hum Mol Genet 18:3987-3996](https://pubmed.ncbi.nlm.nih.gov/19181795/)

[Lammich S, et al. (2014) ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function. Neuron 83:1204-1217](https://pubmed.ncbi.nlm.nih.gov/25002037/)

[Peters F, et al. (2020) α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's Disease. Acta Neuropathol Commun 8:160](https://pubmed.ncbi.nlm.nih.gov/33293482/)

[Tang BL, et al. (2023) Therapeutic potential of ADAM10 modulation in Alzheimer's Disease: a review of the current evidence. Cell Mol Biol Lett 28:44](https://pubmed.ncbi.nlm.nih.gov/37620554/)

[Endres K, Deller T. (2017) Regulation of Alpha-Secretase ADAM10 In vitro and in vivo: Genetic, Epigenetic, and Protein-Based Mechanisms. Front Mol Neurosci 10:56](https://pubmed.ncbi.nlm.nih.gov/28769790/)

[Cuchillo-Ibanez I, et al. (2023) ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels. Int J Mol Sci 24:6113](https://doi.org/10.3390/ijms24076113)

[Kuhn PH, et al. (2010) ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 29:1617-1629](https://pubmed.ncbi.nlm.nih.gov/20852586/)

[Postina R, et al. (2001) A disintegrin-metalloproteinase ADAM10 is implicated in processing of amyloid precursor protein. J Cell Sci 114:3807-3812](https://pubmed.ncbi.nlm.nih.gov/11748852/)

[zur Hove E, et al. (2008) ADAM10 is the major alpha-secretase in the neuronal membrane. J Biol Chem 283:27751-27766](https://pubmed.ncbi.nlm.nih.gov/18003608/)

[Saftig P, et al. (2009) ADAM10 functions in development and disease. Biochim Biophys Acta 1793:1-13](https://pubmed.ncbi.nlm.nih.gov/19027847/)

[Seyfried NT, et al. (2010) ADAM10 and BACE1 activity in brain determines processing of APP. Exp Neurol 225:207-214](https://pubmed.ncbi.nlm.nih.gov/20600196/)

[Deuss M, et al. (2018) ADAM10-mediated ectodomain shedding as therapeutic target. Handb Exp Pharmacol 246:87-108](https://pubmed.ncbi.nlm.nih.gov/29536166/)

Pathway Diagram

The following diagram shows the key molecular relationships involving adam10 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving ADAM10 — A Disintegrin And Metalloproteinase Domain 10 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

ADAM10

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-adam10
kg_node_id	ADAM10
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-946827506176
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-adam10'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

142

Outgoing

70

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ADAM10 — A Disintegrin And Metalloproteinase Domain 10

ADAM10 — A Disintegrin And Metalloproteinase Domain 10

ADAM10 — A Disintegrin And Metalloproteinase Domain 10

Introduction

Gene Information

Protein Structure and Function

Domain Architecture

Catalytic Mechanism

Substrate Specificity

Normal Physiological Functions

Non-Amyloidogenic APP Processing

sAPPα Functions

Competition with BACE1

Notch Signaling

Disease Associations

Alzheimer's Disease

Key Mutations

Therapeutic Implications

Strategies to Enhance ADAM10 Activity

Challenges

Expression Patterns

Brain Expression

Cellular Localization

Regulation

Molecular Pathways

APP Processing Pathway

Signaling Interactions

Animal Models

Key Publications

See Also

External Links

References

Pathway Diagram

Pathway Diagram

💬 Discussion