Insulin‐like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice

  • Pascual‐Lucas M
  • Viana da Silva S
  • Di Scala M
  • et al.
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Abstract

Insulin‐like growth factor 2 (IGF2) was recently found to play a critical role in memory consolidation in rats and mice, and hippocampal or systemic administration of recombinant IGF 2 enhances memory. Here, using a gene therapy‐based approach with adeno‐associated virus ( AAV ), we show that IGF 2 overexpression in the hippocampus of aged wild‐type mice enhances memory and promotes dendritic spine formation. Furthermore, we report that IGF 2 expression decreases in the hippocampus of patients with Alzheimer's disease, and this leads us to hypothesize that increased IGF 2 levels may be beneficial for treating the disease. Thus, we used the AAV system to deliver IGF 2 or IGF 1 into the hippocampus of the APP mouse model T g2576 and demonstrate that IGF 2 and insulin‐like growth factor 1 (IGF1) rescue behavioural deficits, promote dendritic spine formation and restore normal hippocampal excitatory synaptic transmission. The brains of T g2576 mice that overexpress IGF 2 but not IGF 1 also show a significant reduction in amyloid levels. This reduction probably occurs through an interaction with the IGF 2 receptor (IGF2R). Hence, IGF 2 and, to a lesser extent, IGF 1 may be effective treatments for Alzheimer's disease. image An important role for hippocampal insulin‐like growth factor II ( IGF 2) was reported for brain plasticity, learning and memory. This study exploits this finding by reporting the role of IGF 2 in the pathogenesis of Alzheimer´s disease and suggests a possible strategy for therapeutic use. Hippocampal IGF 2 levels are decreased with aging and in pathological conditions related to AD . IGF 2 overexpression in the hippocampus of aged mice enhances memory and prevents dendritic spine loss in CA 1 hippocampal neurons. IGF 2 overexpression in the hippocampus of AD mice reverse memory and synaptic deficits and prevents dendritic spine loss in CA 1 hippocampal neurons. IGF 2 receptor is involved in the extracellular Aβ degradation and suggests that IGF 2 R may be involved in the Aβ clearance observed in IGF 2‐treated T g2576 mice.

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Pascual‐Lucas, M., Viana da Silva, S., Di Scala, M., Garcia‐Barroso, C., González‐Aseguinolaza, G., Mulle, C., … Garcia‐Osta, A. (2014). Insulin‐like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice. EMBO Molecular Medicine, 6(10), 1246–1262. https://doi.org/10.15252/emmm.201404228

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