The Central Nervous System

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A wide variety of therapeutic approaches for T2DM- and AD-related cognitive deficits are under clinical investigation. Therapeutic interventions aimed at rescuing or modifying insulin signaling in the brain should perhaps first be directed at the effects of IGF-I and its ability to modulate brain levels of Aβ. As Aβ is thought to exert inhibitory effects on the insulin signaling pathway, either by acting extracellular or intracellular, IGF-I may represent the most upstream target for both reducing brain Aβ levels and stimulating neurotrophic insulin signaling in patients at risk for developing AD. Consistently, beneficial effects of IGF-I in age- and AD-related brain disturbances have been reported (Lichtenwalner et al., 2001; Markowska et al., 1998; Niikura et al., 2001). Furthermore, IGF-I receptor blockade in the choroid plexus in rodents, triggered brain disturbances that are reminiscent of those found in AD, including amyloidosis, cognitive impairment and hyperphosphorylated forms of tau (Carro et al., 2006). These data possibly link reduced IGF-I receptor signaling in the choroid plexus to AD pathogenesis and associated cognitive defects, and favor the hypothesis that serum IGF-I may have an important role in physiological and pathological brain ageing. Insights into the mechanism of reduced sensitivity to IGF-I at the choroid plexus may help in developing new therapeutic strategies against amyloidosis in the brain and AD-related pathologies. Overall, IGF-I is thought to exert several neuroprotective actions, and regardless of the mechanisms involved, administration of IGF-I may be of therapeutic value in the treatment and more importantly, prevention of brain amyloidosis. Furthermore, based on the success in developing insulin sensitizers for T2DM, drugs aimed at enhancing sensitivity to IGF-I in patients at risk for AD, may already be within reach, as these two hormones share common intracellular pathways.

In the study by De Felice and colleagues (2009), results indicated that the neuroprotective effect of insulin was thought to require an IR signaling-dependent downregulation of synaptic ADDL binding sites (De Felice et al., 2009). Both IR downregulation and synapse loss were markedly reduced in the presence of insulin. Also, the insulin sensitizing drug rosiglitazone was shown to potentiate the ability of insulin to protect synapses against ADDLs (De Felice et al., 2009). These data are again in support of the basis for treatments aimed at stimulating CNS insulin pathways in patients at risk for AD. In agreement, human subjects have been found to respond to administration of intranasal insulin with enhanced declarative memory performance (Benedict et al., 2010; Benedict et al., 2007). Also, several clinical trials have reported that insulin sensitizing drugs such as rosiglitazone attenuate cognitive and memory deficits in both AD and T2DM patients (Landreth, 2007; Landreth et al., 2008; Risner et al., 2006; Ryan et al., 2006; Watson et al., 2005). The underlying mechanisms for these cognitive benefits have not been fully established, although decreased amyloid plaque burden has been hypothesized. Nevertheless, rosiglitazone improves learning and memory in vivo without affecting amyloid deposits (Pedersen et al., 2006). A plausible mechanism of protection is provided by the finding that rosiglitazone potentiates the ability of insulin to protect synapses against ADDL toxicity (De Felice et al., 2009). Taken together, an appealing strategy to protect synaptic memory mechanisms would be to increase the inherent synaptic resistance against ADDLs, while at the same time reducing ADDL abundance. Interestingly, as discussed above, this may be accomplished by increasing sensitivity to IGF-I at the choroid plexus, while also increasing insulin sensitivity with TZDs.

Modulation of insulin signaling as a treatment strategy for T2DM and AD is also imperative with regard to tau pathology. The importance of regulation of GSK-3 as a downstream component of the insulin/AKT signal, has been established by many studies linking GSK-3 to tau pathology, neuronal dysfunction and neurodegeneration. A recent study has shown that a single intrahippocampal injection of a specific Aβ-oligomeric antibody is sufficient to not only clear amyloid pathology, but also tau pathology (Oddo et al., 2006). Moreover, administration of antibodies against the Aβ peptide lead to a decline of soluble Aβ oligomers, but not insoluble Aβ, which correlated with reduced GSK-3 activity and tau phosphorylation in vivo and in vitro (Ma et al., 2006). These data indicate that ADDL oligomers antibodies may protect against the induction of tau pathology and neuronal dysfunction in AD, making the interference of ADDL oligomerization a valid therapeutic target.

In addition, GSK-3 itself may also be a valuable target in treating tau pathology. Lithium is known as a non-specific GSK-3 inhibitor and has been shown to reduce tau pathology in transgenic mice overexpressing mutant tau (Noble et al., 2005). A study by Beaulieu and colleagues suggests that lithium disrupts an AKT-β-arrestin2-protein-phosphatase-2 signaling complex that normally inactivates AKT, thereby stimulating the AKT pathway and inhibiting GSK-3 (Beaulieu et al., 2008). Besides its role in phosphorylation of tau, GSK-3 is also thought to be an essential mediator of apoptosis and regulator of cell survival (Cross et al., 2001; Hetman et al., 2000; Lucas et al., 2001; Pap and Cooper, 1998; Turenne and Price, 2001). These studies strongly suggest that activation of GSK-3 contributes to many forms of apoptosis and that the insulin/AKT pathway may protect neurons by inhibiting GSK-3. In conclusion, protecting neurons against ADDL toxicity may partially rescue insulin signaling in the CNS of individuals at risk for AD, and subsequently reduce tau hyperphosphorylation and associated neuronal dysfunction, as well as improve neuronal viability. Thus, added beneficial effects with regards to neuronal survival and tau pathology, may be obtained with specific inhibition of GSK-3, simultaneously with other components modulating the insulin signaling pathway.