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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

ABSTRACT

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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    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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    • "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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