. NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12867-72. PubMed.

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  1. Antioxidant Defenses—Nitric Oxide, Amyloid-β and Tau Phosphorylation: A Zero Sum Game
    This paper is exceptionally well executed and may lead to a paradigm shift. Dogma indicates that nitric oxide, amyloid-β, and tau phosphorylation are all bad. By deleting nitric oxide synthase 2 (NOS2) in APP transgenic lines, the authors find increased amyloid-β and tau phosphorylation. In our opinion, one can reconcile these data only by viewing nitric oxide, amyloid-β, and tau phosphorylation as protective antioxidants (Smith et al., 2002; Lee et al., 2005; Castellani et al., 2006; Lee et al., 2006). Mutations in APP cause oxidative stress in vitro (Marques et al., 2003), in animal models (Pappolla et al., 1998; Smith et al., 1998), and in humans (Nunomura et al., 2004). Such oxidative stress leads to cellular adaptations, including increases in amyloid-β, tau phosphorylation, and nitric oxide. In the Colton study, by deleting NOS2, remaining cellular adaptations (amyloid-β and tau phosphorylation) are increased, though in this case not sufficiently to prevent neurodegeneration.

    References:

    . Antioxidant protection and neurodegenerative disease: the role of amyloid-beta and tau. Am J Alzheimers Dis Other Demen. 2006 Mar-Apr;21(2):126-30. PubMed.

    . Tau phosphorylation in Alzheimer's disease: pathogen or protector?. Trends Mol Med. 2005 Apr;11(4):164-9. PubMed.

    . Amyloid beta: the alternate hypothesis. Curr Alzheimer Res. 2006 Feb;3(1):75-80. PubMed.

    . Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway. J Biol Chem. 2003 Jul 25;278(30):28294-302. PubMed.

    . Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease. Neurobiol Dis. 2004 Oct;17(1):108-13. PubMed.

    . Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol. 1998 Apr;152(4):871-7. PubMed.

    . Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9. PubMed.

    . Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998 May;70(5):2212-5. PubMed.

  2. Reply to Lee, Perry, Smith, and Zhu
    My colleagues and I are delighted to see the enthusiastic interest in our mouse model for Alzheimer disease. The APPsw NOS2-/- mouse represents a novel approach to understanding the relationship between amyloid and tau pathology. The concept that NO serves as an antioxidant and promotes cell survival has been well developed in a number of physiological systems, such as the cardiovascular system. Thus, it is timely and appropriate that the role of NO as a neuroprotective agent, rather than as an “unrelenting killer” be more thoroughly explored in chronic neurodegenerative diseases. In many ways, the physiological adaptations to a long-lasting disease state are central to this study. As stated by Lee, Perry, Smith, and Zhu, multiple mechanisms including the formation of Aβ may serve to maintain a normal brain redox balance during chronic disease. Through its ability to bind reactive copper, Aβ peptide can serve as a Fenton-type oxidant in the presence of ascorbate (Dikalov et al., 2004) or as an “antioxidant” through modification of its histidine groups (Schoneich, 2004). Thus, what has appeared to be a destructive redox molecule may in fact reduce toxic levels of reactive copper under certain conditions. In our mouse, the ability of nitric oxide to counteract H2O2 and lipid peroxidation is lost, and thus the redox balance is likely to be tipped in favor of oxidation over time, regardless of the source of oxidation. NO’s ability to regulate cGMP, caspases, and kinases, however, greatly extends the level at which NO can alter cell function.

    When and why NO falls and/or NOS fails is of great interest. Both Blaylock and Jansson suggest different, but potentially interesting mechanisms for NOS destruction in the brain. We favor the view that NO is siphoned away initially by reactive scavengers, such as the iron associated with heme oxygenase 1 activity or other reactive NO scavengers. The essential question to neurodegenerative disease, however, is “can NO be successfully replaced and tissue destruction consequently slowed?” The use of NO NSAIDs as described by Gasparini is one such category of agents that have been used. However, in the case of flurbiprofen it may be difficult to separate NO’s contributions from the ferulic acid group. Other therapeutic candidates are clearly being developed by Thatcher and his group. Although we would caution that the ubiquitous nature of NO makes targeting to select tissue locations a critical issue, there is the possibility that useful new therapeutics can be developed from this concept. It would be interesting to know if the incidence and severity of AD are altered in patient populations who have used long-term nitroglycerin as a therapy for cardiovascular disease.

    References:

    . Cupric-amyloid beta peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical. Free Radic Biol Med. 2004 Feb 1;36(3):340-7. PubMed.

    . Selective Cu2+/ascorbate-dependent oxidation of alzheimer's disease beta-amyloid peptides. Ann N Y Acad Sci. 2004 Mar;1012:164-70. PubMed.