This paper seems to skirt many years of autopsy studies finding that the senile plaques have marginal statistical capacity to distinguish normal from AD patients, such as Davis et al., 1999. Also in 1999, Lue et al. concluded that soluble Aβ posed the greatest toxicity, and that Aβ40 was particularly toxic to synapses. But the issue of deposits seems to pale in the face of new MRI studies concerning gross atrophy of the brain, that is, gross death of brain cells and connectivity. See, for example Stroub and colleagues’ 2006 article on MCI. Is the senile plaque issue becoming a tempest in the teapot?

References:
Davis DG, Schmitt FA, Wekstein DR, Markesbery WR, Alzheimer neuropathological alterations in aged cognitively normal subjects, 1999 Apr;58(4):376-88. Abstract

Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel; RE, Rogers J, Soluble amyuloid beta peptide concentration as a predictor of soluble synaptic change in Alzheimer's disease, Am J Pathol,1999 Sept; 155(3):853-62. Abstract

Stroub TR, deToledo-Morrell L, Stebbins, GT, Leurgans S, Bennett DA, Shah RC, Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease, Proc Nat Acad Sci USA, 2006 June; 103(26):10041-45. Abstract

View all comments by Erik Jansson

This report unequivocally demonstrates that Aβ40 and Aβ42 peptides have opposite effects on amyloid deposition in vivo and that Aβ40 inhibits Aβ42-induced amyloidosis. These results nicely complement our data that reducing Aβ40, without increasing Aβ42, leads to accelerated plaque pathology (Deng et al., 2006 and Wang et al., 2006). This is a welcome addition to the Alzforum discussion initiated by Peter Davies and Bart De Strooper last year concerning the pathogenic mechanisms of the PS1 FAD mutations. All data combined support the notion that a partial reduction of Aβ40 (and γ-secretase activity) may be the primary mechanism for the amyloid pathology seen in certain PS1 patients and may indeed apply to sporadic cases, as well.

View all comments by Hui Zheng

Can Some Forms of Aβ Be Good?
The generation of BRI-Aβ40 and BRI-Aβ42 transgenic mice and the crossing of these mice with the Tg2576 APP-transgenic line has enabled Kim and colleagues to determine whether the Aβ40 and Aβ42 peptides could play different roles in plaque deposition. Increasing Aβ40 by crossing BRI-Aβ40 and Tg2576 transgenic mice resulted in decreased plaque deposition, in contrast to the increased deposition previously reported in the BRI-Aβ42/Tg2576 bitransgenic (McGowan et al., 2005). This anti-amyloidogenic “activity” of Aβ40 was confirmed by crossing BRI-Aβ40 with BRI-Aβ42 transgenic mice, which resulted in reduced amyloid deposition relative to BRI-Aβ42 alone. The dramatically decreased plaque number was paralleled by a similar reduction in insoluble, formic acid extractable Aβ, despite an overall increase in total Aβ. The authors then used an in vitro aggregation assay to support their suggestion that decreased amyloid deposition may relate to the ability of Aβ40 to decrease Aβ42 aggregation.

These experiments raise the possibility that Aβ40...  Read more

Can Some Forms of Aβ Be Good?
The generation of BRI-Aβ40 and BRI-Aβ42 transgenic mice and the crossing of these mice with the Tg2576 APP-transgenic line has enabled Kim and colleagues to determine whether the Aβ40 and Aβ42 peptides could play different roles in plaque deposition. Increasing Aβ40 by crossing BRI-Aβ40 and Tg2576 transgenic mice resulted in decreased plaque deposition, in contrast to the increased deposition previously reported in the BRI-Aβ42/Tg2576 bitransgenic (McGowan et al., 2005). This anti-amyloidogenic “activity” of Aβ40 was confirmed by crossing BRI-Aβ40 with BRI-Aβ42 transgenic mice, which resulted in reduced amyloid deposition relative to BRI-Aβ42 alone. The dramatically decreased plaque number was paralleled by a similar reduction in insoluble, formic acid extractable Aβ, despite an overall increase in total Aβ. The authors then used an in vitro aggregation assay to support their suggestion that decreased amyloid deposition may relate to the ability of Aβ40 to decrease Aβ42 aggregation.

These experiments raise the possibility that Aβ40 may be a protective molecule, and emphasize the importance of the Aβ42:Aβ40 ratio as a determinant of amyloid pathology. This is of particular concern as some γ-secretase inhibitors can actually increase the Aβ42:Aβ40 ratio, which could potentially increase plaque deposition despite reducing total Aβ levels. These findings also complement a recent report showing that some presenilin mutations increase amyloid pathology in mice by selectively decreasing Aβ40 without affecting Aβ42 (Deng et al., 2006, and Wang et al., 2006), implicating a potential pathogenic role for decreasing Aβ40.

This paper raises a number of interesting questions. Most importantly, what effect does decreased plaque load in the presence of overall increased Aβ in the BRI-Aβ40 have on behavior, especially the memory deficits observed in Tg2576 mice? This is a central question that bears on the issue of whether Aβ40 is truly protective. It is conceivable that increased levels of soluble Aβ could impair memory performance despite reduced plaque numbers, possibly by increasing the formation of Aβ oligomers. These mice might thus be a valuable resource for identifying the structural forms of Aβ that contribute to memory impairment. Biochemical and behavioral analysis of the BRI-Aβ40/Tg2576 brains may enable more precise information about the roles of Aβ monomers, trimers, oligomers, Aβ*56, protofibrils, and fibrils.

There were hints that the BRI-Aβ40 may have protective effects in addition to preventing plaque deposition, since the BRI-Aβ40/Tg2576 showed somewhat reduced premature death. However, this was not straightforward since the BRI-Aβ40/BRI-Aβ42 bitransgenic showed an even greater increase in premature death. In conclusion, these new observations provide another level of complexity to the Aβ story, and suggest that Aβ by any other name may not be the same.

References:
Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, Dickson DW, Golde T, McGowan E. Abeta40 inhibits amyloid deposition in vivo. J Neurosci. 2007 Jan 17;27(3):627-33. Abstract

McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, Delucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005 Jul 21;47(2):191-9. Abstract

Deng Y, Tarassishin L, Kallhoff V, Peethumnongsin E, Wu L, Li YM, Zheng H. Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology. J Neurosci. 2006 Apr 5;26(14):3845-54. Abstract

Wang R, Wang B, He W, Zheng H. Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology. J Biol Chem. 2006 Jun 2;281(22):15330-6. Epub 2006 Mar 29. Abstract

Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. Epub 2006 Jan 9. Abstract

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View all comments by Bruce Yankner

Amyloid: Getting Less Toxic Every Day
The Alternate Amyloid Hypothesis (1,2), whereby amyloid-β (Aβ) serves as a protective response in the pathogenesis of AD, is supported by this recent paper showing that Aβ is not responsible for the cognitive and pathological changes that are pathognomonic for AD (3). Briefly, in this study, Aβ40 dramatically reduces Aβ deposition (60-90 percent compared with Tg2576 mice) and rescues the premature-death phenotypes of Tg2576 mice. The important question is whether pathological changes observed in Tg2576 mice (e.g., gliosis, synapse degeneration, cognitive deficits) are altered in Aβ40/Tg2576 mice. Interestingly and most importantly, the same research group reported no cognitive improvement in Aβ40/Tg2576 mice compared with Tg2576 mice (4). In this regard, other studies have found that the cognitive function is relatively intact in APP transgenic mice despite massive accumulation of Aβ including soluble and insoluble forms in brain (5,6). Therefore, the role of Aβ in the pathogenesis of AD should be reassessed. It really does appear...  Read more

Amyloid: Getting Less Toxic Every Day
The Alternate Amyloid Hypothesis (1,2), whereby amyloid-β (Aβ) serves as a protective response in the pathogenesis of AD, is supported by this recent paper showing that Aβ is not responsible for the cognitive and pathological changes that are pathognomonic for AD (3). Briefly, in this study, Aβ40 dramatically reduces Aβ deposition (60-90 percent compared with Tg2576 mice) and rescues the premature-death phenotypes of Tg2576 mice. The important question is whether pathological changes observed in Tg2576 mice (e.g., gliosis, synapse degeneration, cognitive deficits) are altered in Aβ40/Tg2576 mice. Interestingly and most importantly, the same research group reported no cognitive improvement in Aβ40/Tg2576 mice compared with Tg2576 mice (4). In this regard, other studies have found that the cognitive function is relatively intact in APP transgenic mice despite massive accumulation of Aβ including soluble and insoluble forms in brain (5,6). Therefore, the role of Aβ in the pathogenesis of AD should be reassessed. It really does appear to be becoming less toxic [sic!] every day.

References:
1. Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, Smith MA. Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann N Y Acad Sci. 2004 Jun;1019:1-4. Review. Abstract

2. 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

3. 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

4. Janus C, Kim J, Hanna A et al. Dissociation between amyloid pathology and memory impairment Alzheimer's & Dementia, 2(3 (Supplement)), S85-S86 (2006).

5. Bizon J, Prescott S, Nicolle MM. Intact spatial learning in adult Tg2576 mice. Neurobiol Aging. 2007 Mar;28(3):440-6. Epub 2006 Feb 28. Abstract

6. Savonenko AV, Xu GM, Price DL, Borchelt DR, Markowska AL. Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE. Neurobiol Dis. 2003 Apr;12(3):194-211. Abstract

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