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

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.

Insulin-like growth factor 2 rescues aging-related memory loss in rats

“…Because IGF-2 crosses the blood brain barrier, it represents a potential therapeutic tool readily available for preclinical testing and clinical trials (Alberini and Chen, 2012; Stern and Alberini, 2013). Our present study using an acute administration of recombinant IGF-2 in rats significantly extends previous knowledge reporting that viral-mediated overexpression of IGF-2 in the hippocampus enhanced memory and promoted dendritic spine formation in aged mice (Pascual-Lucas et al, 2014); first, because recombinant IGF-2 is more readily available and useful in therapeutic settings than brain viral expression, second because we show an effect in another species on aversive and non-aversive tasks, as well as on working memory, and, third, because we provide a mechanism for the decline in IGF-2 during aging, which may suggest a new target for enhancing the effects of IGF-2 and correcting the aging-related changes. In sum, we suggest that IGF-2 may represent an important target for prevention of numerous age-related pathologies.…”

“…In addition, relative to other brain regions, high levels of expression of IGF-2 protein and of its high affinity IGF-2 receptor (IGF-2R) are observed in the adult hippocampus and cortex (Couce et al, 1992; Fernandez and Torres-Alemán, 2012; Hawkes and Kar, 2004; Logan et al, 1994; Ye et al, 2015), brain regions essential for memory consolidation. Notably, both IGF-2 mRNA and mature protein levels are lower in the hippocampus of aged compared to young adult mice (Kitraki et al, 1993; Park and Buetow, 1991; Uddin and Singh, 2013; Pascual-Lucas et al, 2014). Because the effect of IGF-2 as a memory and synaptic plasticity enhancer is robust and very long-lasting, occurs via IGF-2R and not via IGF-1R, and targets multiple domains of hippocampal-dependent memory (Chen et al, 2011; Stern et al, 2014a), here we sought to determine the expression of IGF-2 and IGF-2 receptor (R) in aged rats and whether IGF-2 treatment is effective in preventing age-related memory deficits.…”

The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice

“…GH supplementation to increase serum IGF-1 levels in individuals with childhood onset GH deficiency (Arwert, et al, 2006,Deijen, et al, 1998) or control and mild cognitive impairment individuals (Baker, et al, 2012) is sufficient to improve cognitive performance. Similar results have been observed in rodents following intracerebroventricular, intrahippocampal, peripheral, or brain overexpression delivery of IGF-1 or IGF-2 (Carro, et al, 2006,Chen, et al, 2011,Lopez-Lopez, et al, 2007,Markowska, et al, 1998,Pascual-Lucas, et al, 2014). Mice with a liver specific knockdown of IGF-1 resulting in an 80-85% reduction in serum concentrations show decreased cognitive function at 15-18 months of age but not at 6 months supporting the notion that IGF-1 has a critical role in older brain homeostasis (Svensson, et al, 2006).…”

Viral vectors for therapy of neurologic diseases

“…Other therapeutic approaches to AD gene therapy are more tangential, including AAV delivery of a FK506-binding protein (FKBP1b) that stabilizes Ca++ release from the endoplasmic reticulum in neurons (Gant et al, 2015) or delivery of growth factors that help neurons survive toxic injury, including delivery of cerebral dopamine neurotrophic factor (CDNF) (Kemppainen et al, 2015), insulin growth factor (Pascual-Lucas et al, 2014), brain-derived neurotrophic factor (BDNF; Nagahara et al, 2013) and nerve growth factor (NGF; Tuszynski et al, 2015) to the brain using different virus vectors. The latter has proceeded to promising clinical trials.…”