16 January 2008. Next time you reach for yet another soda, consider this: the habit may put you at risk for more than a bulging midriff and diabetes. Research shows that some of the same factors that increase the risk for type 2, or non-insulin-dependent, diabetes also put people at risk for dementia. Recent papers and a flurry of conference presentations may help scientists understand why. Increased amyloidosis, tau hyperphosphorylation, and vascular and inflammatory pathologies that can exacerbate dementia have all been linked to diabetes. Reduced insulin receptor signaling is also emerging as a correlate of cognitive impairment. For example, in the December 14 Journal of Biological Chemistry, researchers led by Liang Li at the University of Alabama reported that imbibing sucrose-sweetened water exacerbates amyloidosis and memory defects in transgenic animals that overproduce the amyloid-β (Aβ) peptide. In the December 12 Journal of Neuroscience, researchers led by Akihiko Takashima at the Institute for Physical and Chemical Research, Saitama, Japan, report that insulin dysfunction induces hyperphosphorylation of the microtubule-binding protein tau in mice. The two papers support the idea that there may be a link between diabetes/insulin resistance and central players in Alzheimer disease pathology. And at last November’s Society for Neuroscience (SfN) conference in San Diego, California, presentations by Suzanne Craft, University of Washington, Seattle, and Konrad Talbot, University of Pennsylvania, Philadelphia, demonstrated links between microvascular dysfunction and insulin receptor signaling, respectively, and cognitive impairment.

The epidemiologic connection between diabetes and dementia is widely accepted. Just this week, a study in the Archives of Neurology added new data to existing evidence. Scientists led by Lenore Launer at the National Institute on Aging in Bethesda, Maryland, reported that having both diabetes and the ApoE4 allele strongly increased the risk of dementia, specifically AD, in participants of the Cardiovascular Health Study (CHS) Cognition Study (Irie et al., 2008; see also section on ApoE below). However, the relationship between diabetes and dementia may be complex, and there is no consensus on underlying mechanisms. “What is emerging is a picture in which conditions related to insulin deficiency are being identified as very important risk factors for a considerable subset of patients,” Suzanne Craft from the University of Washington, Seattle, told this reporter. So did Jose Luchsinger from Columbia University, New York. “There is no doubt in my mind that diabetes increases the risk of cognitive impairment, just as it increases the risk of heart disease and stroke, but where there are some doubts is whether it is directly linked to AD,” he said (Luchsinger is a co-author on the Takashima paper).

To explore the underlying mechanisms, Li and colleagues tested the relationship between high sugar intake and amyloidosis in APP/PS1 double-transgenic (tg) mice. High dietary sugar, usually in the form of beverages laden with sucrose and high-fructose corn syrup, is widely believed to be a major driving force in the worldwide obesity/diabetes epidemic (see Bray et al., 2004). First author Dongfeng Cao and colleagues offered mice a 10 percent sucrose solution in addition to normal mouse chow. Control mice received water. Over 25 weeks, the sucrose group gained more weight, developed glucose intolerance, high serum insulin, and high serum cholesterol. They performed worse than control tg mice in Morris water maze tests of learning and memory. Though the sugary diet did not change levels of APP or APP processing, total cerebral Aβ and amyloid increased by 3.6-and 2.9-fold, respectively, compared to the control group. The findings imply problems with Aβ degradation or clearance, yet the researchers found no changes in levels of insulin-degrading enzyme (IDE), which also degrades Aβ. In contrast, prior work from Giulio Pasinetti’s group at Mount Sinai School of Medicine, New York, suggested that diet-induced insulin resistance increases γ-secretase processing of Aβ and compromises IDE, leading to increased Aβ burden, in Tg2576 mice; see Ho et al., 2004. The discrepancies remain unresolved at present.

However, Li and colleagues did find that brain levels of ApoE4, an established risk factor for sporadic AD, jumped 2.5-fold in mice on the sugary diet, leading the authors to conclude that “…the up-regulation of apoE accelerated the aggregation of Aβ, resulting in the exacerbation of cerebral amyloidosis in sucrose-treated mice.” How sugar intake and insulin sensitivity relate to the observed increase in ApoE is not clear.

Li and colleagues note that previous work shows that other forms of dietary manipulation, including a high-fat diet, can cause reduced insulin signaling in the brain (see discussion below). Their work adds to a growing literature, including presentations at last year’s SfN meeting from the labs of Marise Parent at Georgia State University, Atlanta (see Abstract), and Robin Kanarek at Tufts University, Medford, Massachusetts (see Abstract), linking sugar intake with learning deficits. Both the Parent and Kanarek labs found that high sugar intake can cause learning deficits in laboratory rats.—Tom Fagan.

See Part 2.

Reference:
Cao D, Lu H, Lewis TL, Li L. Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J. Biol. Chem. 2007 Dec 14;282:36275-36282. Abstract

Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M, Yu WH, Luchsinger JA, Wadzinski B, Duff KE, Takashima A. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J. Neurosci. 2007 Dec 12;27:13635-13648. Abstract