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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    • "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.
    Biochemical and Biophysical Research Communications 09/2014; 453(3). DOI:10.1016/j.bbrc.2014.09.093 · 2.30 Impact Factor
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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.
    Neurobiology of Disease 08/2014; 68. DOI:10.1016/j.nbd.2014.04.018 · 5.08 Impact Factor
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    • "Recently, increased NOX-dependent ROS production in the superior/middle temporal gyri at the earliest clinical manifestations of disease, but not in late-stage AD, was reported (Bruce-Keller et al., 2010). Genetic inactivation of NOX2 in 12- to 15-month-old mice overexpressing the APPsw mutation (Tg2576 mice) results in reduced oxidative damage and rescues both the vascular and behavioral alterations observed in Tg2576 mice (Park et al., 2008). Studies done in cell cultures replicated the postmortem and animal findings on oxidative damage driven by NOX activation. "
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    ABSTRACT: A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich's ataxia and Parkinson's disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS) derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson's disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.
    Frontiers in Pharmacology 03/2014; 5:38. DOI:10.3389/fphar.2014.00038 · 3.80 Impact Factor
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