25 January 2008. Star Trek fans know “resistance is futile.” This, the mantra of the unstoppable, but thankfully fictitious, Borg, is usually heard just before whole races of galactic dwellers are subsumed into the Borg culture. Is it also futile to buck the trend that insulin resistance and dysfunctional insulin/insulin-like signaling contribute to neurodegeneration? Papers in this week’s PNAS online suggest that it may be. Researchers led by Huda Zoghbi, Baylor College of Medicine, Houston, Texas, report that the insulin-like growth factor pathway is altered in two types of ataxia, while a group led by Yadong Huang and Robert Mahley at the Gladstone Institute of Neurological Disease, San Francisco, reports that rosiglitazone, an insulin sensitizer that shows some promise as a cognitive enhancer, boosts dendritic spine density in cortical neurons. Yet a third paper, from Mark Febbraio, Andrea Hevener, and colleagues shows that heat shock protein 72 can protect against insulin resistance in part by limiting activation of Jun kinase, perhaps opening up a new therapeutic angle for treating insulin-related diseases.
Decreased insulin sensitivity is the basis for type 2 diabetes and associated comorbidities, but it is also linked to aging, cognitive decline, and neurodegenerative disorders, such as Alzheimer disease. Epidemiological evidence linking insulin signaling pathways with AD is strong yet complex, and is likely linked to downstream signaling effects (see ARF related news story). Nevertheless, clinical trials of insulin and insulin sensitizers such as rosiglitazone, one of several thiazolidenediones used to treat type 2 diabetes, show some promise in AD patients. Suzanne Craft, University of Washington, Seattle, and colleagues found that rosiglitazone improved cognitive performance in a small pilot trial (see Watson et al., 2005). However, this promising result was not supported by data from a larger trial conducted by researchers at GlaxoSmithKline (see ARF related news story).
In that larger trial there was a hint that patients without an ApoE4 allele might gain some benefit from rosiglitazone, and the Huang and Mahley paper might explain why. First author Jens Brodbeck and colleagues found that ApoE4 and a fragment of the protein (amino acids 1-272) lacking the C-terminal end cause loss of dendritic spines when added to rat primary cortical neurons. Rosiglitazone protects against this loss and also increases spine density when added to primary neurons that are not treated with ApoE. “Our data suggest that rosiglitazone improves cognition by increasing dendritic spine density,” write the authors.
How rosiglitazone leads to an increase in spine number is unclear, but it seems related to the drug’s primary target, the peroxisome proliferator-activated receptor-γ (PPARγ), since Brodbeck and colleagues found that the spine-sparing effect was blocked by the PPARγ antagonist, GW9662. PPARγ agonists have attracted attention as potential AD therapeutics because they are known to increase sensitivity to insulin, reduce the activity of β- and γ-secretases (see Xiong et al., 2007), and reduce inflammation (see recent review by Gary Landreth, 2007). PPARγ agonists also stimulate mitochondria (see ARF related news story), and the authors tap this explanation for the spine rescue. Mitochondria are essential for maintaining synapses (see ARF related news story), and the authors speculate that “rosiglitazone might increase mitochondrial biogenesis or function, thereby improving synaptogenesis or maintenance of dendritic spines.” The reason that the drug delivered no cognitive benefit to patients with the ApoE4 allele might be due to a combination of pathology and pharmacodynamics—the drug does not readily cross the blood-brain barrier. “The low doses of rosiglitazone used in AD patients might not achieve brain levels high enough to overcome the detrimental effects of apoE4 and its fragments despite a potentially compromised blood-brain barrier,” they write.
Mitochondrial dysfunction has also been implicated in Huntington disease (HD), caused by a polyglutamine repeat expansion in the huntingtin protein. In fact, knocking out the PPARγ coactivator PGC-1α in mice causes symptoms akin to HD (see ARF related news story). So it is interesting that researchers led by Howard Hughes Investigator Huda Zoghbi found that insulin-like growth factor signaling is compromised in two other polyglutamine disorders, spinocerebellar ataxias type 1 (SCA1) and type 7 (SCA7).
First author Jennifer Gatchel and colleagues looked for commonalities between SCA1 and SCA7 because among the nine known polyglutamine diseases, these two have most in common. Gatchel used microarray analysis to examine gene expression in mouse models of the two diseases and found 31 genes either up- or downregulated in both. Of these, the data for insulin-like growth factor (IGF) binding protein 5 (Igfbp5) were most statistically significant. The researchers used Northern blots to confirm that this gene was downregulated in both models and found that the repression was progressive. By 40 weeks, transcript levels in the cerebellum were down by 40 percent compared to wild-type mice.
What is the significance of this for ataxias and for neurodegenerative diseases in general? Igfbp5 can prevent activation of the insulin-like growth factor receptor (IGFR) by its ligand, IGF. Loss of Igfbp5 could, therefore, heighten IGF signaling. To test this, Gatchel and colleagues looked in the cerebellum of SCA1 and SCA7 mice for IGFR activation. They found plenty of tell-tale signs. The IGF-1 receptor was phosphorylated in SCA1/SCA7 cerebellum, and when they looked at downstream signaling molecules in SCA1 mice, they also found increased phosphorylation of Akt and Erk, kinases that are activated by insulin and IGF signaling. These changes may reflect an attempt to maximize signaling in the face of mutant ataxin 1 or ataxin 7, suggest the authors. This is very reminiscent of changes that occur in the brains of people with mild cognitive impairment (MCI) and Alzheimer disease. Konrad Talbot and colleagues at the University of Pennsylvania have found that though there is progressive reduction in insulin receptor activation as people progress from MCI to AD, downstream signaling, including phosphorylation of phosphatidyl-inositol-3 kinase, Akt, and GSK-3β, is enhanced (see ARF related news story). Cora O’Neill’s group at University College Cork, Ireland, have reported similar findings (see Griffin et al., 2005). The research suggests that altered insulin or insulin-like growth factor signaling may be associated with the underlying pathology of very different neurodegenerative diseases.
As has been seen with clinical trials of rosiglitazone and insulin itself (see ARF related news story), tackling dysfunctional insulin and insulin-like signaling may have benefits for those suffering from neurodegenerative disease. The third paper, from Mark Febbraio at the Baker Heart Research Institute, Victoria, Australia, Andrea Hevener at the University of California, Los Angeles, and colleagues, suggests a similar therapeutic tack to treat obesity-induced insulin resistance. First author Jason Chung and colleagues found that inducing heat shock protein 72 (Hsp72) or preventing phosphorylation of Jun kinase (JNK) can protect against diet- or obesity-induced insulin resistance.
Patients with type 2 diabetes have reduced expression of Hsp72 and elevated phosphorylation of JNK. This kinase can phosphorylate and deactivate insulin receptor substrate-1, which plays an integral part in insulin receptor signaling. But the authors found that weekly heat therapy (41.5 C for 15 minutes) led to a transient increase in Hsp72 in animals fed a high-fat diet. The therapy also reduced JNK phosphorylation, fasting glucose, and plasma insulin. Overexpressing Hsp72 in skeletal muscle of mice had a similar effect, as did the hydroxylamine derivative BGP-15, which induced Hsp72 in leptin-deficient obese (ob/ob) mice. In these hefty animals BGP-15 also dramatically reduced fasting glucose and insulin levels. While it is not clear from these studies whether induction of Hsp72 might have any benefit in the brain, another hydroxylamine derivative, arimoclomol, was recently shown to delay progression of neurodegeneration in a mouse model of amyotrophic lateral sclerosis (see Kieran et al., 2004). These studies hint that protecting against insulin resistance may prove beneficial for some neurological symptoms in humans. Of course, it may be some time before such a strategy is tested. In the meantime, hot tub anyone?—Tom Fagan.
Brodbeck J, Balestra ME, Saunders AM, Roses AD, Mahley RW, Huang Y. Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons.
Proc Natl Acad Sci U S A. 2008 Jan 22; [Epub ahead of print]
Gatchel JR, Watase K, Thaller C, Carson JP, Jafar-Nejad P, Shaw C, Zu T, Orr HT, Zoghbi HY. The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. PNAS online 2008 January 21. Abstract
Chung J, Nguyen A-K, Henstridge DC, Holmes AG, Chan MHS, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1739-44. Epub 2008 Jan 25. Abstract