There is a fifth possibility - no and yes for which I would vote. My hunch - not more than that - is that the real culprit are the tau tangles. I feel that if there is a common origin relationship between tangles and plaques, it will lead us backwards to the real origin of the condition. If Alois Alzheimer did any disservice, it was that his work tended to focus interest on plaques as such whilst they were really unwitting bystanders.

View all comments by William.G Peberdy

Amyloid-β: A Protective Function
Over the past few years, the vilification of amyloid-β has transcended from scientific hypothesis to religious belief (Lee et al., 2007). Simply put, the scientific evidence now points to amyloid-β being pathognomic but not pathogenic (Castellani et al., 2006b). Nonetheless, it is important to know the function of amyloid-β as well as the mechanisms that lead to increased amyloid-β in Alzheimer disease. To start to address this issue, we have shown that amyloid-β is increased by oxidative stress (Yan et al., 1995), likely as a consequence of increased BACE activity (Tamagno et al., 2002; Tamagno et al., 2005), and that the higher the level of amyloid-β, the lower the level of oxidative stress (Joseph et al., 2001; Nunomura et al., 2001). Since amyloid-β is increased by oxidative stress and, thereafter, is associated with decreased levels of oxidative stress, we suspect that amyloid-β serves an antioxidant function (Smith et al., 2002b; Castellani et al., 2006a; Lee et al., 2006b). As such, removal of amyloid-β, by vaccination or other...  Read more

Amyloid-β: A Protective Function
Over the past few years, the vilification of amyloid-β has transcended from scientific hypothesis to religious belief (Lee et al., 2007). Simply put, the scientific evidence now points to amyloid-β being pathognomic but not pathogenic (Castellani et al., 2006b). Nonetheless, it is important to know the function of amyloid-β as well as the mechanisms that lead to increased amyloid-β in Alzheimer disease. To start to address this issue, we have shown that amyloid-β is increased by oxidative stress (Yan et al., 1995), likely as a consequence of increased BACE activity (Tamagno et al., 2002; Tamagno et al., 2005), and that the higher the level of amyloid-β, the lower the level of oxidative stress (Joseph et al., 2001; Nunomura et al., 2001). Since amyloid-β is increased by oxidative stress and, thereafter, is associated with decreased levels of oxidative stress, we suspect that amyloid-β serves an antioxidant function (Smith et al., 2002b; Castellani et al., 2006a; Lee et al., 2006b). As such, removal of amyloid-β, by vaccination or other means, is likely to exacerbate, not treat disease (Perry et al., 2000; Smith et al., 2002a; Smith et al., 2002c; Lee et al., 2006a).

References:
Castellani RJ, Lee HG, Perry G, Smith MA. 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. Review. Abstract

Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol (Berl). 2006 Jun;111(6):503-9. Epub 2006 Apr 27. Abstract

Joseph J, Shukitt-Hale B, Denisova NA, Martin A, Perry G, Smith MA. Copernicus revisited: amyloid beta in Alzheimer's disease. Neurobiol Aging. 2001 Jan-Feb;22(1):131-46. Review. Abstract

Lee HG, Zhu X, Castellani RJ, Nunomura A, Perry G, Smith MA. Amyloid-{beta} in Alzheimer Disease: The Null Versus the Alternate Hypothesis. J Pharmacol Exp Ther. 2007 Jan 17; [Epub ahead of print] Abstract

Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Amyloid-beta vaccination: testing the amyloid hypothesis?: heads we win, tails you lose! Am J Pathol. 2006 Sep;169(3):738-9. No abstract available. Abstract

Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Amyloid beta: the alternate hypothesis. Curr Alzheimer Res. 2006 Feb;3(1):75-80. Review. Abstract

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. Abstract

Perry G, Nunomura A, Raina AK, Smith MA. Amyloid-beta junkies. Lancet. 2000 Feb 26;355(9205):757. Abstract

Smith MA, Atwood CS, Joseph JA, Perry G. Predicting the failure of amyloid-beta vaccine. Lancet. 2002 May 25;359(9320):1864-5. No abstract available. Abstract

Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9. Review. Abstract

Smith MA, Joseph JA, Atwood CS, Perry G. Dangers of the amyloid-beta vaccination. Acta Neuropathol (Berl). 2002 Jul;104(1):110. Epub 2002 May 16. No abstract available. Abstract

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. Abstract

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. Abstract

Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P, et al. 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. Abstract

View all comments by Rudy Castellani
View all comments by Hyoung-gon Lee
View all comments by Akihiko Nunomura
View all comments by George Perry
View all comments by Mark A. Smith

To use anti-Aβ immunotherapy and other therapeutic strategies targeting Aβ, we must understand the physiological role of this peptide. If Aβ is secreted from healthy neurons in response to activity, and if this peptide downregulates synaptic transmission/neuronal activity (Kamenetz et al., 2003), then we need to understand how antibodies specific to monomeric, oligomeric, or fibrillar Aβ will influence this function.

View all comments by Michael G. Agadjanyan