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The work published by Cohen et al. shows that reduced IGF-1 signaling reduces pathology in a classical mouse model of AD, the double APP/PS1 transgenic mouse. Albeit with several discrepancies, this work largely confirms a previous one by Freude et al. (Freude et al., 2009), where deletion of the IGF-1 receptor in the mouse forebrain also protected against AD pathology. From this evidence one may conclude that reduced IGF-1 signaling is a promising therapeutic strategy in AD.
The notion that the insulin/IGF-1 signaling (IIS) pathway is involved in Alzheimer disease (AD) is gaining momentum (Craft and Watson, 2004; Gasparini and Xu, 2003). However, whether IIS is detrimental or beneficial to the disease is a matter of current debate. Pros and cons abound for each position. Probably the idea that reduced IIS has a general salutary effect stems from the observation in invertebrates that low IIS promotes longevity (Kenyon, 2001). There is also evidence favoring a similar role in mammals, including humans (Suh et al., 2008). It was next ascribed a similar protective role against cancer (LeRoith and Roberts, Jr., 2003). One of the few remaining protective actions of IIS (the other undisputed one is metabolic disturbances) was on the aging and/or diseased brain (Aleman and Torres-Aleman, 2009; Torres-Aleman and Fernandez, 1998).
Indeed, there is evidence for a positive action of IGF-1 on the brain. In a study of growth hormone (GH)-deficient adults, GH was shown to improve cognitive functioning, and Vitiello et al. (2006) reported beneficial effects of six months of GH releasing hormone versus placebo in a group of 89 healthy older (68 years) adults. In the treatment group, IGF-1 levels increased by 35 percent, but only by 1 percent in the placebo group. In addition, increased IGF-1 levels were found of therapeutic benefit in mouse models of AD (Carro et al., 2002; Carro et al., 2006). A positive correlation between serum IGF-1 levels and health status has also been consistently reported in the elderly (Nindl and Pierce, 2010). Furthermore, brain oxidative stress, a pathological disturbance usually linked to AD (Behl et al., 1994), elicits neuronal death through FOXO3 (Lehtinen et al., 2006), a process that requires inhibition of IGF-1 signaling (Davila and Torres-Aleman, 2008), as FOXO3 is downstream of IIS. Confirming this notion is the observation that IGF-1 receptor (IGF-1R) heterozygous mice showed increased neuronal damage in response to MPTP challenge (Nadjar et al., 2008).
However, the observations of Cohen’s and Freude´s labs questions this positive action of IGF-1 in the brain. Both groups used transgenic mice with reduced IGF-1 receptor function cross-bred with classical mouse AD models. The use of transgenic models has been crucial in furthering our understanding of human diseases. However, transgenic models alone are not sufficient to establish pathogenic mechanisms of interest to human diseases. In most cases, these models provide partial information that requires additional experimental approaches, more so when the information provided is contradictory. Thus, while Freude et al. used mice without IGF-1 receptors in forebrain neurons and found reduced Aβ plaque load, Cohen et al. used a mouse with reduced overall IGF-1R content and report increased Aβ plaque load that was equally neuroprotective as it shows lower neurotoxicity. Indeed, they report marked reduction of neuronal death, which is not usually observed in APP/PS1 mice. Notwithstanding the lack of data showing reduced brain IGF-1 signaling in these mice, and assuming that this is the case, the mouse models used express the genetic modifications already from developmental stages. Therefore, it is possible that undetermined compensatory responses develop in these mice to provide protection against AD. Alternatively, elimination of the IGF-1R may not be equivalent to inhibition of IGF-1 signaling only, as IGF-1 may play additional, not yet defined roles.
Nevertheless, the fact that either global or brain-specific reduction of IGF-1R levels similarly protects against AD pathology, together with the reported ambivalent actions of IIS signaling on APP metabolism (Adlerz et al., 2007; Shineman et al., 2009), and the lack of protection against AD after increased IGF-1 levels (Lanz et al., 2007), opens the question of what is the role of IIS in AD. While we will probably agree that IIS has a role in AD, defining it may prove more complex. This may reflect the complexity of this ancient hormonal system. In all probability the key aspect is a balanced IIS function.
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