Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci U S A

Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2008; 105(4):1347-52. DOI: 10.1073/pnas.0711568105
Source: PubMed


Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of Alzheimer's disease (AD), but their role in the amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing the Swedish mutation of the amyloid precursor protein (Tg2576) as a model of AD to examine the role of reactive oxygen species produced by NADPH oxidase in the cerebrovascular alterations, amyloid deposition, and behavioral deficits observed in these mice. We found that 12- to 15-month-old Tg2576 mice lacking the catalytic subunit Nox2 of NADPH oxidase do not develop oxidative stress, cerebrovascular dysfunction, or behavioral deficits. These improvements occurred without reductions in brain amyloid-beta peptide (Abeta) levels or amyloid plaques. The findings unveil a previously unrecognized role of Nox2-derived radicals in the behavioral deficits of Tg2576 mice and provide a link between the neurovascular dysfunction and cognitive decline associated with amyloid pathology.

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Available from: Erin H Norris, Mar 18, 2014
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    • "In the present report, we utilized isolated VSMC monocultures that permit direct measurement of VSMC function, while in our former study[13]we employed isolated cerebral arterioles that permit assessment of both VEC-dependent as well as VECindependent vasomotor function. It is plausible that Aβmediated ROS production has a greater functional impact on VEC than on VSMC, which explain our[13]and others[17,19]past findings that vascular oxidative stress is an important mediator of Aβ-induced CV dysfunction in the setting of intact vessels (ex vivo and in vivo). Our study has several limitations. "
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    ABSTRACT: Background: Substantial evidence suggests that amyloid-β (Aβ) species induce oxidative stress and cerebrovascular (CV) dysfunction in Alzheimer's disease (AD), potentially contributing to the progressive dementia of this disease. The upstream molecular pathways governing this process, however, are poorly understood. In this report, we examine the role of heparan sulfate proteoglycans (HSPG) in Aβ-induced vascular smooth muscle cell (VSMC) dysfunction in vitro. Results: Our results demonstrate that pharmacological depletion of HSPG (by enzymatic degradation with active, but not heat-inactivated, heparinase) in primary human cerebral and transformed rat VSMC mitigates Aβ1-40- and Aβ1-42-induced oxidative stress. This inhibitory effect is specific for HSPG depletion and does not occur with pharmacological depletion of other glycosaminoglycan (GAG) family members. We also found that Aβ1-40 (but not Aβ1-42) causes a hypercontractile phenotype in transformed rat cerebral VSMC that likely results from a HSPG-mediated augmentation in intracellular Ca(2+) activity, as both Aβ1-40-induced VSMC hypercontractility and increased Ca(2+) influx are inhibited by pharmacological HSPG depletion. Moreover, chelation of extracellular Ca(2+) with ethylene glycol tetraacetic acid (EGTA) does not prevent the production of Aβ1-40- or Aβ1-42-mediated reactive oxygen species (ROS), suggesting that Aβ-induced ROS and VSMC hypercontractility occur through different molecular pathways. Conclusions: Taken together, our data indicate that HSPG are critical mediators of Aβ-induced oxidative stress and Aβ1-40-induced VSMC dysfunction.
    Preview · Article · Dec 2016 · Molecular Neurodegeneration
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    • "There are several members in the NADPH oxidase family, among which NOX2 containing NADPH oxidase is highly expressed in cerebral endothelium [10]. Reducing expression of NOX2 can protect mice from a variety of stimuli that produce cerebrovascular dysfunction [11] [12] [13]. 4,4 0 -Diaminodiphenylsulfone (DDS, Dapsone) is currently used to treat leprosy [14] and is known to possess neuroprotective effect against ischemia, spinal cord injury and other brain damage [15] [16] [17] [18] [19]. "
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    ABSTRACT: Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4’-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases.
    Full-text · Article · Sep 2014 · Biochemical and Biophysical Research Communications
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    • "These findings were replicated in both adult and aged APP mice, and are in agreement with normal learning and memory in mice engineered to have prominent Aβ plaque load (Cheng et al., 2007). Our findings are also supported by reports of cognitive recovery with other therapeutic approaches, despite no measured change in the amyloid pathology, for example high soluble Aβ levels in aged Tg2576 AD mice following deletion of the Nox2 NADPH oxidase subunit (Park et al., 2008) or following treatment with COX-2 inhibitors (Kotilinek et al., 2008), and unchanged Aβ plaque load and levels of soluble Aβ 1-40/1-42 (Tong et al., 2012) or Aβ*56 (unpublished data) in adult J20 APP mice after simvastatin treatment. The latter amyloid species, likewise unaffected in our study, refers to the 56-kDa Aβ 1 -42 oligomer linked to memory deficits in Tg2576 AD mice (Lesné et al., 2006) and AD pathogenesis in patients (Lesné et al., 2013). "
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    ABSTRACT: Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer’s disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~ 18 months at endpoint, 3 months treatment) or adult (~ 12 months at endpoint, 10 months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [18 F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and upregulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.
    Full-text · Article · Aug 2014 · Neurobiology of Disease
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