Two new animal models may help researchers clarify the link between diabetes and Alzheimer disease (AD). Researchers in Japan have crossed an AD mouse (APP23) with two types of diabetic cousins, the leptin-deficient obese mouse (ob/ob) and the spontaneously diabetic NSY mouse. As senior author Ryuichi Morishita of Osaka University and colleagues report in this week’s PNAS online, offspring from both crosses have poorer learning and memory than either of their parental strains, but without producing any more amyloid-β (Aβ) than do APP23 mice. The findings suggest that diabetic mice are more sensitive to Aβ pathology, which jibes with recent data from human patients. Interestingly, the diabetic profile is exaggerated in both crosses as well, indicating that AD pathology, in turn, exacerbates diabetes. “The ob/ob mouse is a fairly good model of type 2, insulin resistance-related diabetes. The fact that they see additive effects is a really interesting phenomenon,” suggested Suzanne Craft, University of Washington, Seattle.
Scientists have known for some time that type 2 diabetes increases the risk for Alzheimer disease, but exactly how the two conditions are linked is still unclear. “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,” according to one industry commentator who requested anonymity to avoid lengthy internal review (see full comment below).
First author Shuko Takeda and colleagues report that the cognition of APP23-ob/ob mice declines rapidly. At eight weeks old, both APP23 and ob/ob parental strains perform just as well as wild-type animals in the Morris water maze, cutting the time to find the hidden platform from about 75 seconds to 25 seconds over nine training sessions. But the APP23-ob/ob mice perform poorly already. Remarkably, at the ninth training session, they take as long to find the platform as they did on the first attempt. By 12 weeks of age, they perform no better, and even have difficulty finding the platform when it is in plain view above the murky water. The authors do not think poor vision explains why these animals have trouble finding raised platforms because, after three training sessions, they gradually do improve and are able to find the platform as quickly as control wild-type animals do on the first attempt.
One might think that the poor cognitive skills of the APP23-ob/ob mice could be due to greater production of Aβ in the brain as a quirk of the diabetic co-morbidity. But while the brain weighed less in 12-month-old animals than in their age-matched APP23 parents, neither strain had developed amyloid plaques in the hippocampus by that age. And though faint plaques appeared in the entorhinal cortex of both strains, total Aβ levels were no different between the two. Where Aβ may enter the picture, though, is through the blood vessels. More Aβ40 deposited in vessels of six-month-old APP23-ob/ob mice compared to APP23 controls. Whether this cerebral amyloid angiopathy (CAA) is related to the eight- and 12-week cognitive deficits is unclear. Interestingly, recent work from Suzanne Craft and colleagues suggests that diabetes sensitizes humans to Aβ pathology. That’s because dementia patients with diabetes seem to have lower Aβ burden than dementia patients free of diabetes (see ARF related news story on Sonnen et al., 2009). While Craft did not look at CAA pathology in those cases, she did find that dementia patients with diabetes had a greater number of microinfarcts, indicative of blood vessel disease. “The role of CAA in dementia is very interesting, and we don’t have a good handle on that yet in humans. This study points to some very interesting possibilities that could be investigated,” she told ARF. (For a recent review on the link between vascular risk factors, diabetes, and cognition, see Knopman and Roberts, 2010.)
One potential nexus is RAGE, or receptor for advanced glycation end products. It both mediates diabetic pathology and binds Aβ (see ARF related news story). Takeda and colleagues found that, compared to the age-matched parental strain, RAGE is elevated in the blood vessels of three-month-old APP23-ob/ob mice. Interleukin 6 (IL-6) and tumor necrosis factor α were elevated in microvessels of the brain, as well, and this is in keeping with RAGE activation setting off an inflammatory response. Astrogliosis was also prominent in these young APP23-ob/ob mice. Finally, that Aβ binds RAGE might explain why these animals have worse diabetic pathology, including higher glucose intolerance and reduced insulin sensitivity, than ob/ob parents. However, Craft also pointed out that Aβ can bind the insulin receptor. “High levels of Aβ could interfere with insulin receptor binding processes and might contribute to insulin resistance,” she said.
The ob/ob mouse is a well-accepted model of type 2 diabetes. Still, the animals differ from humans with type 2 diabetes in having a leptin deficiency and a very early emergence of pathology. This raises the possibility that leptin loss, rather than diabetes per se, may directly contribute to the phenotype, note Takeda and colleagues. However, the researchers found similar exacerbations of pathology when they crossed APP23 mice with NSY (Nagoya-Shibata-Yasuda) animals. These were developed by selective breeding of animals that show spontaneous glucose intolerance, and their diabetic features emerge with age. “Though this strain is not as widely used, it does seem to capture age-related insulin resistance, or type 2 diabetes,” suggested Craft.
Takeda and colleagues report that both glucose tolerance and insulin sensitivity are reduced in 12-week-old APP23-NSY crosses compared to NSY parents. Interestingly, while different lines of offspring had different Aβ40 levels, those levels correlated with the extent of glucose intolerance, suggesting a direct link between Aβ and metabolic dysfunction. In addition, feeding the animals a high-fat diet inflamed brain microvasculature in APP23-NSY mice (but not NSY animals), as judged by IL-6 immunoreactivity, and a deterioration in performance in the Morris water maze that was not apparent in the parental strain. These aggravated readouts emerged without any increase in total brain Aβ.
Results from both sets of crosses indicate an intimate and complex relationship between diabetes and dementia, with diabetes perhaps leading to increased CAA and dementia aggravating metabolic hallmarks of diabetes. The emergence of cognitive deficits in APP23-NSY mice on a high-fat diet may be particularly germane to human conditions. “We’ve been thinking that there has got to be a gene-environment interaction that is critical in humans, and the one that seems to make the most intrinsic sense is some diet-related factor,” suggested Craft. This work also fits with an emerging consensus from biomarker research that Aβ pathology represents a sign of impending AD, and that diabetes and/or vascular disease reflect factors that limit one’s resistance to overt expression of dementia.—Tom Fagan