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

Maria Pascual‐Lucas,Mar Cuadrado‐Tejedor,Gloria González‐Aseguinolaza,Marianna Di Scala,Carolina Garcia‐Barroso,Christophe Mulle,Silvia Viana Da Silva,Ana Garcia‐Osta,Cristina M Alberini

doi:10.15252/emmm.201404228

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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia in the elderly
We studied whether the overexpression of hippocampal insulin-like growth factor 2 (IGF2) could enhance memory in aged WT mice compared to the overexpression of insulin-like growth factor 1 (IGF1)
amyloid b (Ab) has recently been shown to precisely bind IGF2 receptor (IGF2R) domain 11, which would suggest that IGF2R may act as an Ab scavenger (Murakoshi et al, 2013). These results demonstrate for the first time, to our knowledge, that IGF2/IGF2R is involved in the extracellular Ab degradation mechanism, and suggest that IGF2R may be involved in the Ab clearance observed in associated viral (AAV)-IGF2-injected Tg2576 mice

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. There is currently no efficacious treatment for the disease. Several studies show that the accumulation of soluble forms of Ab correlates with synapse dysfunction and loss (Shankar et al, 2007), which appears to occur relatively early in the disease, prior to cell death. Systemic treatments with IGF2 significantly enhance hippocampal-cortical-dependent memories, including those known to be impaired in rodent models of AD (Stern et al, 2014). This would suggest that IGF2 is an interesting candidate for the treatment of cognitive impairment in AD. The formation and maturation of synapses in the hippocampus, a mechanism that is impaired in AD (Jacobsen et al, 2006; Smith et al, 2009; Ricobaraza et al, 2012) and depends on IGF2/IGF2R signalling, may underlie the IGF2-dependent memory enhancement effect (Schmeisser et al, 2012)

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Conclusion