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

EMBO Molecular Medicine

Maria Pascual-Lucas¹  Silvia Viana da Silva²  Marianna Di Scala³  Carolina Garcia-Barroso¹  Gloria González-Aseguinolaza³  Christophe Mulle²  Cristina M Alberini⁴  Mar Cuadrado-Tejedor¹ 

[1] Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain;Interdisciplinary Institute for Neuroscience, Université of Bordeaux, CNRS UMR 5297, Bordeaux, France;Gene Therapy and Hepatology Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain;Center for Neural Science, New York University, New York, NY, USA

关键词: Alzheimer's disease;    IGF1;    IGF2;    IGF2R;    synaptic plasticity;   

DOI  :  10.15252/emmm.201404228

来源: Wiley

【 摘 要 】

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 IGF2 enhances memory. Here, using a gene therapy-based approach with adeno-associated virus (AAV), we show that IGF2 overexpression in the hippocampus of aged wild-type mice enhances memory and promotes dendritic spine formation. Furthermore, we report that IGF2 expression decreases in the hippocampus of patients with Alzheimer's disease, and this leads us to hypothesize that increased IGF2 levels may be beneficial for treating the disease. Thus, we used the AAV system to deliver IGF2 or IGF1 into the hippocampus of the APP mouse model Tg2576 and demonstrate that IGF2 and insulin-like growth factor 1 (IGF1) rescue behavioural deficits, promote dendritic spine formation and restore normal hippocampal excitatory synaptic transmission. The brains of Tg2576 mice that overexpress IGF2 but not IGF1 also show a significant reduction in amyloid levels. This reduction probably occurs through an interaction with the IGF2 receptor (IGF2R). Hence, IGF2 and, to a lesser extent, IGF1 may be effective treatments for Alzheimer's disease.

Synopsis

An important role for hippocampal insulin-like growth factor II (IGF2) was reported for brain plasticity, learning and memory. This study exploits this finding by reporting the role of IGF2 in the pathogenesis of Alzheimer´s disease and suggests a possible strategy for therapeutic use.

• Hippocampal IGF2 levels are decreased with aging and in pathological conditions related to AD.
• IGF2 overexpression in the hippocampus of aged mice enhances memory and prevents dendritic spine loss in CA1 hippocampal neurons.
• IGF2 overexpression in the hippocampus of AD mice reverse memory and synaptic deficits and prevents dendritic spine loss in CA1 hippocampal neurons.
• IGF2 receptor is involved in the extracellular Aβ degradation and suggests that IGF2R may be involved in the Aβ clearance observed in IGF2-treated Tg2576 mice.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.