Neuronal and Vascular Oxidative Stress in Alzheimer’s Disease

The brain is a highly metabolically active organ producing large amounts of reactive oxygen species (ROS). These ROS are kept in check by an elaborate network of antioxidants. Although ROS are necessary for signaling and synaptic plasticity, their uncontrolled levels cause oxidation of essential macromolecules such as membrane lipids, nucleic acids, enzymes and cytoskeletal proteins. Indeed, overproduction of ROS and/or failure of the antioxidant network lead to neuronal oxidative stress, a condition associated with not only aging but also Alzheimer’s disease (AD). However, the specific source of excessive ROS production has not yet been identified. On one hand, amyloid beta (Aβ) has been extensively shown to act as an oxidant molecule. On the other hand, oxidative stress has been shown to precede and exacerbate Aβ pathology. This review will address the involvement of oxidative stress in the context of neuronal as well as vascular dysfunction associated with AD

Hyperglycemia Induces Oxidative Stress and Impairs Axonal Transport Rates in Mice

studies to determine the effect of hyperglycemia on the neurons in the central nervous system (CNS). While olfactory dysfunction is indicated in diabetes, the effect of hyperglycemia on olfactory receptor neurons (ORNs) remains unknown. In this study, we utilized manganese enhanced MRI (MEMRI) to assess the impact of hyperglycemia on axonal transport rates in ORNs. We hypothesize that (i) hyperglycemia induces oxidative stress and is associated with reduced axonal transport rates in the ORNs and (ii) hyperglycemia-induced oxidative stress activates the p38 MAPK pathway in association with phosphorylation of tau protein leading to the axonal transport deficits.-weighted MEMRI imaging was used to determine axonal transport rates post-streptozotocin injection in wildtype (WT) and superoxide dismutase 2 (SOD2) overexpressing C57Bl/6 mice. SOD2 overexpression reduces mitochondrial superoxide load. Dihydroethidium staining was used to quantify the reactive oxygen species (ROS), specifically, superoxide (SO). Protein and gene expression levels were determined using western blotting and Q-PCR analysis, respectively.STZ-treated WT mice exhibited significantly reduced axonal transport rates and significantly higher levels of ROS, phosphorylated p38 MAPK and tau protein as compared to the WT vehicle treated controls and STZ-treated SOD2 mice. The gene expression levels of p38 MAPK and tau remained unchanged.Increased oxidative stress in STZ-treated WT hyperglycemic mice activates the p38 MAPK pathway in association with phosphorylation of tau and attenuates axonal transport rates in the olfactory system. In STZ-treated SOD-overexpressing hyperglycemic mice in which superoxide levels are reduced, these deficits are reversed

Mitochondrial Superoxide Contributes to Blood Flow and Axonal Transport Deficits in the Tg2576 Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive decline in cognitive functions and the deposition of aggregated amyloid beta (Abeta) into senile plaques and the protein tau into tangles. In addition, a general state of oxidation has long been known to be a major hallmark of the disease. What is not known however, are the mechanisms by which oxidative stress contributes to the pathology of AD.In the current study, we used a mouse model of AD and genetically boosted its ability to quench free radicals of specific mitochondrial origin. We found that such manipulation conferred to the AD mice protection against vascular as well as neuronal deficits that typically affect them. We also found that the vascular deficits are improved via antioxidant modulation of the endothelial nitric oxide synthase, an enzyme primarily responsible for the production of nitric oxide, while neuronal deficits are improved via modulation of the phosphorylation status of the protein tau, which is a neuronal cytoskeletal stabilizer.These findings directly link free radicals of specific mitochondrial origin to AD-associated vascular and neuronal pathology

STZ- WT mice depict significantly increased ROS levels that decrease in]SOD2-STZ mice.

<p>(A) The images depict nasal cavity sections showing genotypic differences in DHE fluorescence. (B) The graph depicts ratio of DHE and corresponding DAPI fluorescence, which was measured with ImageJ software. Significance was assessed by one way ANOVA with Dunnett's post-test. For WT, WT-STZ, SOD2, and SOD2-STZ n = 4, 6, 4, 4 respectively. ** p<0.01, * p<0.05 Bar = 20 µm.</p

MEMRI experiments demonstrate that the axonal transport deficits in WT-STZ mice recover in SOD2-STZ mice.

<p>(A) Pseudo-color MRI images depicting changes in Mn²⁺ signal intensities (yellow color) at the beginning (2minutes) and at the end of the imaging session (32 minutes) at a region of interest (ROI) identified as a circle on the outer olfactory neuronal layer (ONL). Note that the WT, SOD and SOD2-STZ mice exhibit a change from green (2 minute time point) to yellow (32 minute time point) whereas the WT-STZ animals exhibit a light green color at both time points indicating that Mn²⁺ has not traveled to these areas at the same rate. (B) Gray-Scale Image of the same data set in (A). (C) The graph depicts normalized axonal transport rates (% control) in the WT and SOD2 mice treated with vehicle or STZ for a week before <i>in vivo</i> axonal transport studies. Twelve mice were used in the WT group and four mice were used in each of WT-STZ, SOD2, and SOD2-STZ groups. Statistical analysis: One way ANOVA, Dunnett's post-test. * p<0.05. SOD2  =  SOD-2 overexpressing mice; SOD2-STZ  =  SOD-2 overexpressing mice treated with STZ.</p

STZ-induced hyperglycemia impairs axonal transport in the olfactory receptor neurons.

<p>(A) Graph depicts axonal transport rates (depicted as Mn²⁺ ΔSI/t on Y axis, where “SI” is signal intensity and “t” is time) of Mn²⁺at 1 week post-STZ treatment for WT(n = 3) and WT-STZ with fasting glucose levels 200–399 mg/dl (n = 3), and >400 mg/dl (n = 5). (B) Graph depicts the changes in axonal transport rates for WT (n = 4), WT-STZ (n = 3), and WT-STZ+insulin treated mice (n = 4). (C) The graph represents changes in axonal transport rates in a mouse model of WT-STZ (n = 5) as compared to WT mice (n = 4). Statistical analysis: One way ANOVA, Tukey's post test for more than 2 groups and Students t test to compare 2 groups. * p<0.05, ** p<0.01, *** p<0.001/WT  =  wildtype control. WT-STZ  =  Wildtype treated with streptozotocin.</p