Abstract
Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer’s disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (−/−) mice. p66Shc (−/−) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (−/−) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.
Highlights
Worldwide, as the population of the ages and life expectancy increases, the number of people with dementia is increasing
To generate an animal model of diabetes-impaired cognitive function for assessment of working memory and learning ability, we first examined whether cognitive impairment could develop in type 1 (STZinduced diabetic mice) and type 2 diabetes animal models using the radial arm water maze (RAWM) test
At 22 weeks, STZtreated mice had an increased mean number of errors on one acquisition trial and on the retention trial compared with vehicle-treated mice (Fig. 1F). These data indicate that both type 1 and type 2 diabetes models develop working memory and learning deficits in an age dependent manner that is fully consistent with previous reports[17,18,19]
Summary
As the population of the ages and life expectancy increases, the number of people with dementia is increasing. A number of reports showed that changes in life style and these related diseases could increase future dementia risk[2]. P66Shc (−/−) diabetic mice showed significant amelioration of cognitive dysfunction, as well as decreased levels of OS and inflammatory markers. We found that these markers were associated with microglia-mediated neurotoxicity. This study postulates a p66Shc-mediated OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment. To our knowledge, this is the first study showing a direct molecular association between OS and diabetes-related cognitive decline
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