Intake of Sucrose-sweetened Water Induces Insulin Resistance and Exacerbates Memory Deficits and Amyloidosis in a Transgenic Mouse Model of Alzheimer Disease
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
01/2008; 282(50):36275-82. DOI: 10.1074/jbc.M703561200
Compelling evidence indicates that excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. Type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). High fat diets promote AD-like pathology in mice. It is not known whether consumption of excess sugar as in calorically sweetened beverages with an otherwise normal diet affects the development of AD. In the present study, we provided 10% sucrose-sweetened water to a transgenic mouse model of AD with a normal rodent diet. Compared with the control mice with no sucrose added in the water, the sucrose group gained more body weight and developed glucose intolerance, hyperinsulinemia, and hypercholesterolemia. These metabolic changes were associated with the exacerbation of memory impairment and a 2-3-fold increase in insoluble amyloid-beta protein levels and deposition in the brain. We further showed that the levels of expression and secretase-cleaved products of amyloid-beta precursor protein were not affected by sucrose intake. The steady-state levels of insulin-degrading enzyme did not change significantly, whereas there was a 2.5-fold increase in brain apoE levels. Therefore, we concluded that the up-regulation of apoE accelerated the aggregation of Abeta, resulting in the exacerbation of cerebral amyloidosis in sucrose-treated mice. These data underscore the potential role of dietary sugar in the pathogenesis of AD and suggest that controlling the consumption of sugar-sweetened beverages may be an effective way to curtail the risk of developing AD.
Available from: Young-Ji Shiao
- "ch can further hinder cerebral MRglu and cognitive function . The MWM is a classic task for assessing hippocampal - dependent spatial memory ( Bromley - Brits et al . , 2011 ) . Longer escape times during the training phase of the MWM in HFD - treated Tg 2576 mice and sucrose - treated APP / PS1 AD mice are associated with an increased Ab burden ( Cao et al . , 2007 ) . We found no difference in the escape latencies between NCD AD and HFSTZ AD mice during the training phase of the MWM , suggesting that this task is not sufficiently sensitive to detect an impact of HFSTZ treatment on the hippocampus - dependent learning and memory during the early stage of APP / PS1 mice ( Chen et al . , 2012 ) ."
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ABSTRACT: Although metabolic syndrome was suggested to be a risk factor for Alzheimer's disease (AD), the role of metabolic stress in the initiation of AD pathology remains unclear. In this study, metabolic stress was induced by a high-fat diet and low-dose injection of streptozotocin (HFSTZ) before the appearance of senile plaques in APP/PS1 transgenic mice. We found that, HFSTZ treatment exacerbated amyloid beta burden and astrocyte activation in the vicinity of plaques. Moreover, we observed an upregulation of astrocytic S100B expression in the brain parenchyma of HFSTZ-treated APP/PS1 mice concurrent with increased interleukin-6 expression in cerebral microvascular cells. To determine the impact of HFSTZ treatment on brain function, we performed [(18)F]fludeoxyglucose-positron emission tomography and analyzed nesting behavior. HFSTZ treatment impaired nest construction and cerebral glucose metabolism in several brain regions of APP/PS1 mice during the early stage of AD. These results suggest that HFSTZ-induced peripheral metabolic stress may contribute to vascular inflammation and astrocyte reactivity in the parenchyma and may impair activity of daily living skill and cerebral glucose metabolism in APP/PS1 mice.
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Available from: Michael P McDonald
- "We did not conduct a cued-platform control task for several reasons. First, we and others have already shown that the APP/PSEN1 mice have robust spatial learning impairments in the water maze but are unimpaired on the non-spatial cued control task (Bernardo et al., 2007; Cao et al., 2007; Cohen et al., 2009; Harrison et al., 2009b; Harrison et al., 2010; Lewis et al., 2010). Second, the transgenics also exhibit deficits in cognitive flexibility (Arrazola et al., 2009; Reiserer et al., 2007; Toledo and Inestrosa, 2010), a putatively frontally-mediated cognitive process involved in, e.g., switching learning modalities from cued to spatial. "
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ABSTRACT: Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer's disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7 months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r 2 = .959), but uncorrelated in transgenics (r 2 = .013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics' deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Aβ40 and Aβ42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. β-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Aβ. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways.
Available from: Catia Ribeiro
- "The presence of amyloid(A ) plaques in the brains of APP/PS1 mice has been observed as early as 4 months of age and plaque numbers increase with age . These mice exhibit memory deficits  , as well as evidence of enhanced microglial activation . Recent evidence has indicated that blood-brain barrier (BBB) permeability is increased with age and in APP/PS1 mice  , and this is accompanied by the presence of IFN-producing peripheral immune cells in the brain . "
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ABSTRACT: Macrophages are key cells in tissue defense in the periphery and, under certain circumstances, infiltrate the central nervous system, where they may play a similar role in the brain, perhaps supporting the function of microglia. Macrophages have been shown to adopt different activation states in response to various stimuli. Specifically, when exposed to inflammatory stimuli such as interferon (IFN)γ, the cells adopt the M1 phenotype, whereas when exposed to anti-inflammatory cytokines such as interleukin (IL)-4 or IL-13, the M2 phenotype is adopted. While M1 macrophages are associated with tissue defense and destruction of invading pathogens, M2 macrophages are involved in tissue repair and in terminating inflammation. It is well known that an inflammatory microenvironment exists in the brain of aged animals and also in the brain of mice that overexpress amyloid-β protein precursor (AβPP) and presenilin 1 (PS1; AβPP/PS1 mice), a commonly-used model of Alzheimer's disease (AD). Recent studies have revealed that immune cells, including macrophages, infiltrate the brain in both circumstances raising the possibility that these cells adopt the M1 activation state and contribute to the already-existing neuroinflammation. We set out to examine the responses of bone marrow-derived macrophages prepared from wildtype and AβPP/PS1 mice and demonstrate that cells from AβPP/PS1 mice, even after several days in culture, respond more profoundly to IFNγ than those from wildtype mice. We suggest that this propensity to respond to M1-polarizing stimuli, together with the described changes in the brain of AβPP/PS1 mice, contribute to the development of chronic neuroinflammation.
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