| Symbol |
ADAM10 |
| Full Name |
A Disintegrin And Metalloproteinase Domain-Containing Protein 10 |
| Chromosome |
15q21.3 |
| NCBI Gene |
102 |
| Ensembl |
ENSG00000137845 |
| OMIM |
602192 |
| UniProt |
O14672 |
| Diseases |
Alzheimer's Disease |
| Expression |
Cerebral cortex, Hippocampus, Cerebellum, Thalamus |
p.Q170H (LOAD; ↓α
p.R181G (LOAD; ↓α
p.Tyr167* (nonsense; FAD) |
¶ ADAM10 — ADAM Metallopeptidase Domain 10
Adam10 (Alpha Secretase) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
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 [amyloid precursor protein[/genes/app ([APP[/genes/app. By cleaving APP within the [amyloid-beta[/entities/amyloid-beta ([Aβ[/entities/amyloid-beta domain, ADAM10 precludes the generation of [Amyloid-Beta[/entities/amyloid-beta
peptides, making it a key protective factor against Alzheimer's Disease (AD) [1][2].
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 [1][3]. ADAM10's α-secretase activity represents a major therapeutic target: enhancing ADAM10-mediated APP processing shifts the balance away from amyloidogenic β-secretase ([BACE1[/entities/bace1
-
Non-amyloidogenic APP processing: ADAM10 cleaves APP between residues Lys687 and Leu688 (within the Aβ sequence), generating soluble APPα (sAPPα) and the membrane-bound C-terminal fragment α (CTFα/C83). This cleavage precludes Aβ generation because it cuts within the Aβ peptide domain [1][3].
-
sAPPα production: The released sAPPα ectodomain has neuroprotective and neurotrophic properties, promoting neuronal survival, synaptic plasticity, and memory formation. sAPPα also has anti-inflammatory effects [4].
-
Competition with BACE1: ADAM10 and BACE1 (β compete for APP substrate at the cell surface and in endosomes. The relative activity of these two enzymes determines the balance between amyloidogenic (Aβ-producing) and non-amyloidogenic pathways — a balance that is central to the amyloid hypothesis of AD [2][4].
ADAM10 is a promiscuous "sheddase" that cleaves the ectodomains of numerous transmembrane proteins:
- Notch receptors: Required for Notch signaling pathway activation
- N-cadherin and E-cadherin: Important for cell adhesion and synaptic remodeling
- EphA/ephrin ligands: Involved in axon guidance and synapse formation
- [TREM2[/genes/trem2: ADAM10 sheds the ectodomain of [TREM2[/entities/trem2, generating soluble TREM2 (sTREM2), a biomarker of microglial activation in AD
- Prion protein: Cleaves PrP in the central region
ADAM10 is synthesized as a 748-amino-acid zymogen with the following domains:
- 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 [2].
- Metalloproteinase domain: Contains the catalytic zinc-binding motif (HEXXHXXGXXH) that mediates substrate cleavage
- Disintegrin domain: Participates in substrate recognition and cell-cell interactions
- Cysteine-rich domain: Mediates protein-protein interactions
- Transmembrane domain and cytoplasmic tail: Anchors the enzyme and regulates trafficking/activity
- Cerebral [cortex[/brain-regions/cortex (all layers)
- [hippocampus[/brain-regions/hippocampus (CA1, CA3, dentate gyrus)
- Cerebellum
- Thalamus
- Basal ganglia
Expression data is available from the Allen Human Brain Atlashttps://human.brain-map.org/microarray/search/show?search_term=ADAM10.
ADAM10 mutations are linked to Alzheimer's Disease through loss of α-secretase function:
Prodomain Missense Mutations (Late-Onset AD):
- p.Q170H: Found in 7 late-onset AD families. Reduces α-secretase activity by >70% and elevates Aβ levels 1.5–3.5-fold in cell-based assays [1]. Impairs the intramolecular chaperone function of the ADAM10 prodomain, leading to improper enzyme folding and maturation [2].
- p.R181G: Found in 4 late-onset AD families (combined with Q170H across 11 of 16 affected individuals from 7 families, average onset age 69.5 years). Similarly reduces α-secretase activity and elevates Aβ [1][2].
Nonsense Mutation (Familial AD):
- p.Tyr167*: A heterozygous nonsense mutation identified in a family with both early and late-onset AD. Results in a truncated, non-functional ADAM10 protein [3].
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 [2].
ADAM10 is a prime therapeutic target for AD because enhancing its activity could simultaneously reduce toxic Aβ production and increase neuroprotective sAPPα levels [4]:
- Transcriptional upregulation: Retinoids, melatonin, and certain nuclear receptor agonists (PPARγ, LXR, RXR) can increase ADAM10 gene expression [4][1].
- BACE1 inhibition: Reducing β-secretase activity indirectly favors α of APP. However, clinical trials of BACE1 inhibitors have faced challenges due to off-target effects [4].
- Acitretin (vitamin A derivative): A retinoid that upregulates ADAM10 in patients; showed increased CSF sAPPα in a phase II trial [4].
- Etazolate (EHT 0202): A GABA-A receptor modulator that stimulates ADAM10-mediated α-secretase activity; tested in phase II clinical trials for AD.
- Epigenetic modulation: [HDAC[/entities/hdac-enzymes inhibitors can derepress ADAM10 promoter activity [1].
- ADAM10 has numerous substrates beyond APP, raising concerns about off-target effects of broad ADAM10 activation (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
- [Genes Index[/genes — All gene pages
- [Proteins Index[/proteins — Protein pages
- [Alzheimer's disease[/diseases/alzheimers — Neurodegenerative disease
The study of Adam10 (Alpha Secretase) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- [Potential late-onset Alzheimer's Disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity. . DOI
- [ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function. . DOI
- α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's Disease. DOI
- [Therapeutic potential of ADAM10 modulation in Alzheimer's Disease: a review of the current evidence. . DOI
- Endres K, Deller T. Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms. Frontiers in Molecular Neuroscience, 2017;10:56. DOI https://doi.org/10.3389/fnmol.2017.00056
- [Cuchillo-Ibanez I, et al. ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels. International Journal of Molecular Sciences, 2023;24(7:6113. . DOI
- Kuhn PH, et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the [amyloid precursor protein[/entities/app-protein in primary [neurons[/entities/neurons. EMBO Journal, 2010;29(17):3020-3032. DOI https://doi.org/10.1038/emboj.2010.167
- [NCBI Gene: [ADAM10[/genes/adam10https://www.ncbi.nlm.nih.gov/gene/102)
- [OMIM: [602192]https://omim.org/entry/602192)## See Also
-
- [BACE1 (Beta-Secretase)[/entities/bace1 {
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