. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7036-41. PubMed.

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  1. [Editor's note: The Alzforum occasionally allows industry scientists to post comments without attribution to avoid lengthy internal review requirements.]

    Takeda et al. have made a very important step forward in capturing the interaction between type 2 diabetes and Alzheimer disease in a transgenic animal model. This work provides a great opportunity to identify the mechanisms by which insulin resistance accelerates dementia symptoms and similarly to explain how APP metabolism exacerbates the diabetic phenotype.

    Building on evidence from Suzanne Craft, Siegfried Hoyer, Greg Cole, Suzanne de la Monte, and others, Dr. Morishita and colleagues have tested a specific hypothesis that peripheral insulin resistance causes a rapid deterioration in cognitive function in mice that overexpress APP. Eight-week-old double-transgenic mice (APP+ - ob/ob) show a profound deficit in the Morris water maze that is not observed in either single transgenic line. The inability of these mice to learn the water maze cannot be explained by diabetes-induced visual impairment. Intriguingly, this deficit is apparent prior to plaque deposition, and levels of soluble and insoluble Aβ were found to be indistinguishable from the APP23 parental line.

    Importantly, the authors support this finding in a second mouse model of diabetes (NSY mice). The effect is much less pronounced in this model, perhaps because the NSY mice have impaired peripheral insulin secretion, while ob/ob mice show severe insulin insensitivity due to a deficiency in leptin signaling in the hypothalamus.

    Nevertheless, the authors clearly demonstrate that the two diseases are interacting. For instance, Aβ shows an accelerated deposition along the cerebral vasculature, and RAGE, which has been implicated in both diabetes and AD pathology, is upregulated by three months of age. Similarly, APP overexpression induced an increase in circulating glucose and a profound insulin insensitivity compared to the ob/ob parental line. A key piece to this puzzle may prove to be the further suppression of brain insulin in double-transgenic mice (Figure 4).

    The authors identify several other hallmarks of Alzheimer disease not typically seen in APP transgenic mice. These include reduced cholinergic innervation of the hippocampus, decreased brain weight, and astrogliosis. It will be important to see whether MAPT/tau is abnormally phosphorylated and if there is overt cell loss in older animals. It will also be interesting to learn how these animals respond to treatment with glitazones, DPPIV antagonists or γ-secretase inhibitors.

  2. The elegant paper by Takeda et al. demonstrates that crossing APP-overexpressing mice with leptin-deficient mice, a model of a metabolic syndrome including hyperglycemia, exacerbates the cognitive decline observed in APP mice (APP23). The effect was observed without changes in brain Aβ burden, but cerebrovascular amyloid deposition and associated inflammation were enhanced in the APP-ob/ob mice. Considering that cerebrovascular dysfunction is present both with defective leptin signaling (Didion et al., 2005) and in APP mice (Iadecola et al., 1999), the data suggest that the added alterations in the blood supply to the brain may play a role in the cognitive worsening of the APP-ob/ob crosses.

    This conclusion is supported by experiments in APP mice crossed with NOX2-null mice in which rescuing the cerebrovascular dysfunction ameliorated cognitive performance without altering the amyloid load (Park et al., 2008). Therefore, modulation of the brain blood supply can influence, positively or negatively, the cognitive outcome in these models independently of the amyloid load. The authors were careful to consider the possibility that alterations in insulin signaling could also play a role. Furthermore, other metabolic effects of leptin deficiency (hyperlipidemia, hypotension, etc.; see Kennedy et al., 2010) could also have influenced the outcome of these studies. Nevertheless, the findings of Takeda et al. broaden our understanding of the effect of cardiovascular risk factors on amyloid pathology, and raise the possibility that therapeutic interventions targeted to cerebral blood vessels may be beneficial in Alzheimer disease.

    References:

    . Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes. Stroke. 2005 Feb;36(2):342-7. PubMed.

    . SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci. 1999 Feb;2(2):157-61. PubMed.

    . Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1347-52. PubMed.

    . Mouse models of the metabolic syndrome. Dis Model Mech. 2010 Mar-Apr;3(3-4):156-66. PubMed.

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