ADAM10 — A Disintegrin And Metalloproteinase Domain 10

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

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). By cleaving APP within the amyloid-beta domain, ADAM10 precludes the generation of toxic amyloid-beta peptides, making it a key protective factor against Alzheimer’s Disease (AD) ^{1Potential late-onset Alzheimer's Disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity2009 · Hum Mol Genet · DOI 10.1093/hmg/ddp323 · PMID 19181795Open reference2ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function2014 · Neuron · DOI 10.1016/j.neuron.2014.06.032 · PMID 25002037Open reference}.

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 ^{3α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's Disease2020 · Acta Neuropathol Commun · DOI 10.1186/s13195-020-00708-0 · PMID 33293482Open reference}. 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 ^{4Therapeutic potential of ADAM10 modulation in Alzheimer's Disease: a review of the current evidence2023 · Cell Mol Biol Lett · DOI 10.1186/s12964-023-01072-w · PMID 37620554Open reference}.

Gene Information

Protein Structure and Function

Domain Architecture

ADAM10 is synthesized as a 748-amino-acid zymogen with the following domain structure ^{5ADAM10 functions in development and disease2009 · Biochim Biophys Acta · PMID 19027847Open reference}:

1. 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 ^{2ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function2014 · Neuron · DOI 10.1016/j.neuron.2014.06.032 · PMID 25002037Open reference}.

2. 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.

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

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

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

6. 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:

1. Zinc-bound water molecule: Acts as the nucleophile

2. Glu²⁴² (general base): Activates the water molecule

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

4. Met²³⁶ (Met-turn): Provides structural support

Substrate Specificity

ADAM10 is a promiscuous “sheddase” that cleaves the ectodomains of numerous transmembrane proteins ^{6ADAM10-mediated ectodomain shedding as therapeutic target2018 · Handb Exp Pharmacol}:

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 ^{7A disintegrin-metalloproteinase ADAM10 is implicated in processing of amyloid precursor protein2001 · J Cell Sci · PMID 11748852Open reference8ADAM10 is the major alpha-secretase in the neuronal membrane2008 · PMID 18003608Open reference}.

sAPPα Functions

The released sAPPα ectodomain has multiple neuroprotective properties:

1. Neurotrophic effects: Promotes neuronal survival and differentiation

2. Synaptic plasticity: Enhances LTP and memory formation

3. Anti-inflammatory: Modulates microglial activation

4. Anti-oxidant: Reduces oxidative stress

5. 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 ^{9ADAM10 and BACE1 activity in brain determines processing of APP2010 · Exp Neurol · PMID 20600196Open reference}. 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 ^{2ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function2014 · Neuron · DOI 10.1016/j.neuron.2014.06.032 · PMID 25002037Open reference}0:

1. Initial cleavage by ADAM10 (extracellular domain shedding)

2. 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 ^{2ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function2014 · Neuron · DOI 10.1016/j.neuron.2014.06.032 · PMID 25002037Open reference}1.

Therapeutic Implications

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

1. Reduce toxic Aβ production

2. 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 ^{2ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function2014 · Neuron · DOI 10.1016/j.neuron.2014.06.032 · PMID 25002037Open reference}2:

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

2. Prodomain processing: Furin-mediated activation

3. Trafficking: RAB GTPases regulate movement to membrane

4. 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

1. Kim M, et al. (2009) Potential late-onset AD-associated mutations in ADAM10 attenuate alpha-secretase activity. Hum Mol Genet 18:3987-3996

2. Lammich S, et al. (2014) ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation. Neuron 83:1204-1217

3. Peters F, et al. (2020) α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial AD. Acta Neuropathol Commun 8:160

4. Tang BL, et al. (2023) Therapeutic potential of ADAM10 modulation in AD. Cell Mol Biol Lett 28:44

5. Endres K, Deller T. (2017) Regulation of ADAM10 in vitro and in vivo. Front Mol Neurosci 10:56

6. Kuhn PH, et al. (2010) ADAM10 is the physiologically relevant α-secretase in neurons. EMBO J 29:1617-1629

See Also

• Alzheimer’s Disease

• APP (Amyloid Precursor Protein)

• Amyloid-beta

• BACE1

• Alpha-secretase

• sAPPα

• Secretase Pathway

External Links

• NCBI Gene: ADAM10

• UniProt: O14672

• Ensembl: ENSG00000137845

• Allen Human Brain Atlas: ADAM10

• OMIM: 602192