Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice

Trueba-Saiz, Ángel; Cavada, Carmen; Fernández, Adolfo; Leon, Thomas Y.Y.; González, David; Fortea, Juan; Lleó, Alberto; Ser, Teodoro del; Núñez, Ángel; Torres‐Alemán, Ignacio

doi:10.1038/tp.2013.102

Cited by 68 publications

(63 citation statements)

References 38 publications

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“…IGF-1, to our knowledge, has not yet been found effective in enhancing memory in healthy conditions (Stern et al 2014). However, studies in both humans and rodent models reported a rescuing effect of IGF-1, as well as insulin or IGF-2, on cognitive functions in pathological conditions, particularly in cerebrovascular alterations and its role in aging and AD (Liu et al 2001, 2004; Carro et al 2002; Fernandez and Torres-Aleman 2012; Torres-Aleman 2012; Johansson et al 2013; Trueba-Saiz et al 2013), suggesting that IGF-1 and IGF-2 act via distinct mechanisms. Although IGF-1 has been reported to improve memory deficits in aging the data are controversial (for excellent reviews of this subject see Deak and Sonntag 2012 and Sonntag et al 2012).…”

Section: Discussionmentioning

confidence: 99%

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

Steinmetz

Johnson

Iannitelli

et al. 2016

Neurobiology of Aging

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Aging is accompanied by declines in memory performance, and particularly affects memories that rely on hippocampal-cortical systems, such as episodic and explicit. With aged populations significantly increasing, the need for preventing or rescuing memory deficits is pressing. However, effective treatments are lacking. Here we show that the level of the mature form of insulin-like growth factor 2 (IGF-2), a peptide regulated in the hippocampus by learning, required for memory consolidation and a promoter of memory enhancement in young adult rodents, is significantly reduced in hippocampal synapses of aged rats. By contrast the hippocampal level of the immature form proIGF-2 is increased, suggesting an aging-related deficit in IGF-2 processing. In agreement, aged compared to young adult rats are deficient in the activity of proprotein convertase 2, an enzyme that likely mediates IGF-2 post-translational processing. Hippocampal administration of the recombinant, mature form of IGF-2 rescues hippocampal-dependent memory deficits as well as working memory impairment in aged rats. Thus, IGF-2 may represent a novel therapeutic avenue for preventing or reversing aging-related cognitive impairments.

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Section: Discussionmentioning

confidence: 99%

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

Steinmetz

Johnson

Iannitelli

et al. 2016

Neurobiology of Aging

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“…However, several studies in both humans and rodent models have shown a rescuing effect of IGF1, as well as insulin or IGF2, on cognitive functions in pathological conditions, particularly in mild cognitive impairment or Alzheimer's disease (AD) with insulin (Born et al 2002;Reger et al 2006Reger et al , 2008Sims-Robinson et al 2010), and on cerebrovascular alterations, aging and AD with IGF1 (Liu et al 2001(Liu et al , 2004Carro et al 2002;Craft et al 2012;Fernandez and Torres-Aleman 2012;Torres Aleman 2012;Johansson et al 2013;Trueba-Saiz et al 2013).…”

Section: Discussionmentioning

confidence: 99%

The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation

2014

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Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms.

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“…Studies have demonstrated that increasing levels of circulating IGF1 lowers amyloid b (Ab) levels in the brain (Carro et al, 2002). This effect may be the result of the reduced serum-to-cerebrospinal fluid (CSF) traffic of IGF1 reported in both patients with AD (Johansson et al, 2013) and AD mouse models (Trueba-Saiz et al, 2013). However, other authors have demonstrated that reducing IGF1 receptor signalling protects against Ab toxicity in different AD models (Cohen et al, 2009;Freude et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice

Cited by 68 publications

References 38 publications

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

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

The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation

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

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