. Thromboxane receptor activation mediates isoprostane-induced increases in amyloid pathology in Tg2576 mice. J Neurosci. 2008 Apr 30;28(18):4785-94. PubMed.

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  1. Comment by Mark A. Smith, Akihiko Nunomura, Paula Moreira, Xiongwei Zhu, Rudy J. Castellani, Hyoung-gon Lee, George Perry

    Oxidative Stress and Amyloid-β: A STOP SIGN, Not a Vicious Cycle
    Unlike in the not-so-distant, controversial past (Mattson et al., 1995; Smith et al., 1995), there is now almost complete acceptance of a role of oxidative stress in the pathogenesis of Alzheimer disease (AD). In fact, we believe oxidative stress is one of, if not the, earliest events in disease (Nunomura et al., 2001). Moreover, as noted in this study using isoprostanes, which are elevated in AD (Casadesus et al., 2007), oxidative stress can drive increases in amyloid-β (Yan et al., 1995). This latter event is likely mediated by increased APP expression as well as by increased BACE and other secretases (Tamagno et al., 2002; Tamagno et al., 2005; Tamagno et al., 2008), and it indicates that amyloid-β is a response to oxidative stress. Conventional wisdom would suggest that such amyloid-β thereafter propagates oxidative stress and sets up a vicious cycle. Unfortunately, such wisdom ignores the fact that increases in amyloid-β are associated with either decreased (Nunomura et al., 2001) or stabilized (Pratico et al., 2001) levels of oxidative stress with increasing amyloid-β. As such, amyloid-β is likely a protective response to oxidative stress. It serves as a STOP sign to oxidative stress.

    While not wanting to be the messengers of doom (Perry et al., 2000; Smith et al., 2002), under such circumstances, removing amyloid-β is likely to increase oxidative stress and exacerbate disease. Such an interpretation does not bode well for Bapineuzumab from Elan/Wyeth, which is in ongoing Phase 2/3 clinical trials (Castellani et al., 2007).

    See also:

    Castellani R, Lee HG, Perry G, Smith MA, Zhu X (2007) Comment: Amyloid spin doctors. Alzheimer Research Forum.

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