| Gene Symbol | IGF2 |
| Common Names | Insulin-like growth factor 2, Somatomedin-A |
| Protein | [IGF2 Protein](/proteins/igf2-protein) |
| Location | 11p15.5 |
| NCBI Gene ID | 3481 |
| UniProt | [P01344](https://www.uniprot.org/uniprot/P01344) |
| Aliases | IGF-II, C11orf43, PP9974 |
Insulin-like growth factor 2 (IGF2) is a peptide hormone and growth factor that plays critical roles in fetal development, brain development, and adult neuroprotection.[1] Along with IGF1, IGF2 is one of two primary insulin-like growth factors in mammals. IGF2 exhibits neurotrophic, neuroprotective, and metabolic effects in the central nervous system, making it relevant to neurodegenerative disease pathophysiology.[2]
IGF2 is a 7.5 kDa protein sharing structural homology with insulin and IGF1. The IGF2 gene is subject to genomic imprinting, with expression primarily from the paternal allele in most tissues.[3] In the adult brain, IGF2 expression is found in:
IGF2 signals primarily through the IGF1 receptor (IGF1R) and the insulin receptor isoform A (IR-A), with binding to IGF2R acting as a clearance mechanism.[5]
IGF2 serves multiple physiological functions:
Fetal Development: Essential for embryonic and fetal growth, particularly CNS development.[6]
Neurogenesis: Promotes neural stem cell proliferation and differentiation in the dentate gyrus.[7]
Synaptic Plasticity: Enhances long-term potentiation (LTP) and memory consolidation.[8]
Neuroprotection: Protects neurons from various insults including excitotoxicity and oxidative stress.[9]
Metabolic Regulation: Modulates glucose metabolism and energy homeostasis in the brain.[10]
Myelination: Supports oligodendrocyte function and myelin maintenance.[11]
IGF2 has complex and sometimes contradictory roles in Alzheimer's disease:
Neuroprotection: IGF2 reduces amyloid-beta toxicity and tau hyperphosphorylation in cellular and animal models.[12]
Memory Enhancement: IGF2 administration enhances hippocampal-dependent memory and reverses memory deficits in AD models.[13]
Amyloid Clearance: IGF2 may promote clearance of amyloid-beta via enhanced insulin-degrading enzyme activity.[14]
Reduced Levels: Some studies report decreased IGF2 in AD brains and CSF, though findings are inconsistent.[15]
The insulin/IGF signaling axis is increasingly recognized as dysfunctional in AD, with some researchers proposing AD as "type 3 diabetes" due to brain insulin resistance.[16]
In Parkinson's disease, IGF2 shows neuroprotective potential:
IGF2 expression is increased in surviving dopaminergic neurons, suggesting a compensatory response.[18]
IGF2, along with IGF1, has been investigated in ALS:
IGF2 levels decline with age, and reduced IGF signaling may contribute to age-related cognitive decline.[20] IGF2 supplementation in aged animals improves memory performance, suggesting therapeutic potential for age-related cognitive disorders.[21]
Several therapeutic strategies targeting IGF2 are being explored:
Recombinant IGF2: Direct administration has shown neuroprotection in preclinical models but faces challenges with blood-brain barrier penetration.[22]
IGF2 Gene Therapy: AAV-mediated IGF2 delivery to the hippocampus improves memory in animal models.[23]
IGF2 Enhancers: Small molecules that increase endogenous IGF2 expression are under investigation.[24]
Combination Therapy: IGF2 combined with IGF1 or other growth factors may provide synergistic benefits.[25]
| Variant | rsID | Effect | Disease Association |
|---|---|---|---|
| ApaI | rs17202060 | Altered expression | Growth disorders |
| -884G>A | rs680 | Paternal transmission | AD risk (controversial) |
| 820G>A | Variable expression | Cognitive aging |
IGF2 interacts with multiple pathways relevant to neurodegeneration:
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Hawkes C, Kar S. [The insulin-like growth factor-II/mannose-6-phosphate receptor](https://doi.org/10.1016/S0165-0173(03). Brain Research Reviews. 2004. ↩︎
Giannoukakis N, et al. Genomic imprinting of IGF2. Proceedings of the National Academy of Sciences. 1993. ↩︎
Bondy CA, Lee WH. [IGF2 in the central nervous system](https://doi.org/10.1016/0165-0173(93). Trends in Neurosciences. 1993. ↩︎
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Bracko O, et al. IGF2 promotes adult hippocampal neurogenesis. Cell Stem Cell. 2012. ↩︎
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Guan J, et al. IGF2 protects against neuronal injury. Neurochemistry International. 2004. ↩︎
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Ye P, et al. IGF2 in oligodendrocyte development and myelination. Journal of Neuroscience. 2002. ↩︎
Duron E, et al. Insulin/IGF signaling in Alzheimer's disease. Ageing Research Reviews. 2011. ↩︎
Stern SA, et al. A local increase in IGF2 rescues memory deficits. Nature. 2014. ↩︎
Farris W, et al. Insulin-degrading enzyme and Alzheimer's disease. Proceedings of the National Academy of Sciences. 2003. ↩︎
Tham A, et al. [Insulin-like growth factors in Alzheimer's disease](https://doi.org/10.1016/0304-3940(93). Neuroscience Letters. 1993. ↩︎
de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes. Journal of Alzheimer's Disease. 2008. ↩︎
Wilczak N, et al. [IGF2 in Parkinson's disease](https://doi.org/10.1016/S1474-4422(03). The Lancet Neurology. 2003. ↩︎
Offen D, et al. IGF2 expression in Parkinson's disease. Neuroscience Letters. 2009. ↩︎
Lepore AC, et al. IGF2 and ALS. Neurobiology of Disease. 2007. ↩︎
Sonntag WE, et al. [Age-related changes in IGF signaling](https://doi.org/10.1016/S0531-5565(99). Experimental Gerontology. 1999. ↩︎
Pardo J, et al. IGF2 reverses age-related memory decline. Journal of Neuroscience. 2014. ↩︎
Liu JP, et al. Recombinant IGF2 for neuroprotection. Neuron. 2009. ↩︎
Stern SA, et al. Hippocampal IGF2 gene therapy improves memory. Nature. 2011. ↩︎
Agis-Balboa RC, et al. Small molecules enhancing IGF2 expression. Molecular Psychiatry. 2019. ↩︎
Kaspar BK, et al. Combination IGF therapy for neurodegeneration. Science. 2003. ↩︎
Yakar S, et al. IGF2 and glucose homeostasis. Diabetes. 2076. ↩︎