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).
Casadesus G, Smith MA, Basu S, Hua J, Capobianco DE, Siedlak SL, Zhu X, Perry G.
Increased isoprostane and prostaglandin are prominent in neurons in Alzheimer disease.
Mol Neurodegener. 2007;2:2.
PubMed.
Mattson MP, Carney JW, Butterfield DA.
A tombstone in Alzheimer's?.
Nature. 1995 Feb 9;373(6514):481.
PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA.
Oxidative damage is the earliest event in Alzheimer disease.
J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67.
PubMed.
Perry G, Nunomura A, Raina AK, Smith MA.
Amyloid-beta junkies.
Lancet. 2000 Feb 26;355(9205):757.
PubMed.
Praticò D, Uryu K, Leight S, Trojanoswki JQ, Lee VM.
Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis.
J Neurosci. 2001 Jun 15;21(12):4183-7.
PubMed.
Smith MA, Atwood CS, Joseph JA, Perry G.
Predicting the failure of amyloid-beta vaccine.
Lancet. 2002 May 25;359(9320):1864-5.
PubMed.
Smith MA, Sayre LM, Vitek MP, Monnier VM, Perry G.
Early AGEing and Alzheimer's.
Nature. 1995 Mar 23;374(6520):316.
PubMed.
Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M.
Oxidative stress increases expression and activity of BACE in NT2 neurons.
Neurobiol Dis. 2002 Aug;10(3):279-88.
PubMed.
Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, Perry G, Jo DG, Mattson MP, Tabaton M.
Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein.
J Neurochem. 2008 Feb;104(3):683-95.
PubMed.
Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M.
Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways.
J Neurochem. 2005 Feb;92(3):628-36.
PubMed.
Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P.
Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide.
Nat Med. 1995 Jul;1(7):693-9.
PubMed.
Comments
Jikei University School of Medicine
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.
References:
Casadesus G, Smith MA, Basu S, Hua J, Capobianco DE, Siedlak SL, Zhu X, Perry G. Increased isoprostane and prostaglandin are prominent in neurons in Alzheimer disease. Mol Neurodegener. 2007;2:2. PubMed.
Mattson MP, Carney JW, Butterfield DA. A tombstone in Alzheimer's?. Nature. 1995 Feb 9;373(6514):481. PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.
Perry G, Nunomura A, Raina AK, Smith MA. Amyloid-beta junkies. Lancet. 2000 Feb 26;355(9205):757. PubMed.
Praticò D, Uryu K, Leight S, Trojanoswki JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001 Jun 15;21(12):4183-7. PubMed.
Smith MA, Atwood CS, Joseph JA, Perry G. Predicting the failure of amyloid-beta vaccine. Lancet. 2002 May 25;359(9320):1864-5. PubMed.
Smith MA, Sayre LM, Vitek MP, Monnier VM, Perry G. Early AGEing and Alzheimer's. Nature. 1995 Mar 23;374(6520):316. PubMed.
Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002 Aug;10(3):279-88. PubMed.
Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, Perry G, Jo DG, Mattson MP, Tabaton M. Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem. 2008 Feb;104(3):683-95. PubMed.
Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem. 2005 Feb;92(3):628-36. PubMed.
Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P. Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med. 1995 Jul;1(7):693-9. PubMed.
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