Nimmrich V, Grimm C, Draguhn A, Barghorn S, Lehmann A, Schoemaker H, Hillen H, Gross G, Ebert U, Bruehl C.
Amyloid beta oligomers (A beta(1-42) globulomer) suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents.
J Neurosci. 2008 Jan 23;28(4):788-97.
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The link among activated caspases, tangles, and death of neurons has been proposed based on snapshot types of analyses of patient brain, mouse brain, and cells. Experimental evidence for a causal relation was lacking, as most data did not surpass the “chicken-egg” level. It is unclear what is cause, consequence, or correlation.
The Spires-Jones et al. study takes care of that, although only on a short time scale. The most recent study by the group of Michel Goedert goes in the same direction, and does so on a longer time scale (Delobel et al., 2008). Both groups conclude that caspases are unlikely to contribute to tauopathy.
We have assessed in the past, and occasionally still do, in our different transgenic AD models how activated caspases relate to amyloid and tau pathology. We were unable to find a close correlation, also not in the p25 mice in which neurons degenerate “in droves” (Muyllaert et al., 2008). Activated caspase is also not part of the picture in our most recent “combined” Alzheimer model, i.e., bigenic APPxTau mice with amyloid and tau pathology. Moreover, in that same study, we compare with TauxGSK3 bigenic mice (biGT mice) that develop tangles in almost every forebrain neuron with aging, but without killing the neurons (Terwel D, Muyllaert D, Dewachter I, Borghgraef P., Croes S., Devijver H., Van Leuven F., Amyloid activates GSK-3 to aggravate neuronal tauopathy in bigenic mice Am J Pathol. 2008, March issue).
The central issue in AD of “Do tangles kill neurons?,” raised again by Spires-Jones et al., can now be answered with a firm no. On the contrary, the hypothesis that “tangles are protective” gains in weight and might be true, after all! Our upcoming paper on the bigenic mice reinforces this view further.
In summary: tangle formation in itself does not activate caspases. Contributions of activated caspases to neuronal cell death does not involve truncation of tau. Tau truncation in itself is not involved in promoting tangle formation, and tangle formation in itself is not causing cell death. Clearly, other factors, yet to be identified, must exist in the complex chain of events leading to neuronal death.
Negative results are important to exclude “candidates” and stop hypotheses. The new data, even if “they come only out of mouse models,” should inspire us to rethink the AD problem, and invite new hypotheses and new candidates to come forward.
Delobel P, Lavenir I, Fraser G, Ingram E, Holzer M, Ghetti B, Spillantini MG, Crowther RA, Goedert M.
Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy.
Am J Pathol. 2008 Jan;172(1):123-31.
Muyllaert D, Terwel D, Kremer A, Sennvik K, Borghgraef P, Devijver H, Dewachter I, Van Leuven F.
Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration.
Am J Pathol. 2008 Feb;172(2):470-85. Epub 2008 Jan 17
Aβ1-42 globulomers (1) are synthetic soluble Aβ42 oligomers, which are interesting entities because they are relatively homogeneous. The major species runs at 48kDa by SDS-PAGE. There are minor species at 38kDa and 20kDa. A monoclonal antibody with relative specificity for globulomers, 8F5, stains in a halo-like pattern around Tg2576 plaques, and tends to stain the periphery of AD plaques. This is different from the staining pattern of the A11 antibody developed in the Glabe lab, which does not stain thioflavin S-positive plaques (2). In addition, Aβ1-42 globulomers bind to cultured neurons in a punctuate manner, similar in appearance to the pattern observed with ADDLs (Aβ-derived diffusible ligands, a different synthetic Aβ oligomer preparation), which have been shown to colocalize with dendritic spine proteins (3). However, Aβ globulomers differ from Aβ*56, an endogenous high-n Aβ oligomeric assembly of 56 kDa (4). For instance, differences reside in the electrophoretic and chromatographic profile using SDS-PAGE and gel filtration, and in their relative levels in Tg2576 mice at 2, 10, and 12 months of age. The levels of Aβ1-42 globulomers are low and approximately the same at 2 and 10 months, then rise ~fourfold at 12 months (1). These findings appear to mirror Aβ deposition occurring in Tg2576 mice (5,6). In contrast, the levels of Aβ*56 are undetectable at 2 months, and are the same at 10 and 12 months (4), except for a ~2-week interval around 12 months when Aβ*56 levels decrease as the rate of amyloid deposition increases in the brain of Tg2576 mice (6). Very importantly, the levels of Aβ*56 negatively correlate with spatial memory function in Tg2576 mice. Since the measured levels of Aβ1-42 globulomers do not correspond with poorer cognitive performance in Tg2576 mice, their relevance to memory loss is unclear, at least as can be assessed in this transgenic model of AD. Instead, the staining pattern of Aβ1-42 globulomers around plaques is reminiscent of the toxic halo that has been described in the Hyman lab (7-10).
In this latest report, the authors demonstrate that Aβ1-42 globulomers suppress spontaneous synaptic activity in hippocampal primary neurons. They further refined their studies using pharmacological approaches and showed that in-vitro application of Aβ1-42 globulomers altered calcium influx through presynaptic P/Q-type calcium channels (Cav2.1). The globulomer-induced inhibition of calcium influx was rescued by roscovitine, recently proposed to positively regulate P/Q-type Ca2+ channels by acting on their extracellular domain, independently of its ability to inhibit the neuron-specific cyclin-dependent kinase Cdk5. These electrophysiological findings concerning globulomers could potentially explain the asynchrony of electrical activity that researchers in the Hyman lab described around plaques (8-10). Unlike ADDLs and secreted Aβ oligomers from APP-overexpressing cells (3,11,12), the punctuate staining pattern in cultured neurons suggests that the Aβ globulomers do not bind to postsynaptic spines, since the electrophysiological findings point to presynaptic P/Q channels being their site of action. This observation would not support the authors’ hypothesis that “all Aβ oligomers target the same synaptic mechanism.” On the contrary, if true, the collective data on various forms of Aβ to date indicate that they can target different synaptic elements.
Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, Bahr M, Schmidt M, Bitner RS, Harlan J, Barlow E, Ebert U, Hillen H.
Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease.
J Neurochem. 2005 Nov;95(3):834-47.
Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG.
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
Science. 2003 Apr 18;300(5618):486-9.
Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL.
Synaptic targeting by Alzheimer's-related amyloid beta oligomers.
J Neurosci. 2004 Nov 10;24(45):10191-200.
Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH.
A specific amyloid-beta protein assembly in the brain impairs memory.
Nature. 2006 Mar 16;440(7082):352-7.
Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG.
Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease.
J Neurosci. 2001 Jan 15;21(2):372-81.
Lesné S, Kotilinek L, Ashe KH.
Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function.
Neuroscience. 2008 Feb 6;151(3):745-9.
Urbanc B, Cruz L, Le R, Sanders J, Ashe KH, Duff K, Stanley HE, Irizarry MC, Hyman BT.
Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):13990-5.
Stern EA, Bacskai BJ, Hickey GA, Attenello FJ, Lombardo JA, Hyman BT.
Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques.
J Neurosci. 2004 May 12;24(19):4535-40.
Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT.
Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy.
J Neurosci. 2005 Aug 3;25(31):7278-87.
Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Jones PB, Stern EA, Bacskai BJ, Hyman BT.
Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model.
Am J Pathol. 2007 Oct;171(4):1304-11.
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL.
Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine.
J Biol Chem. 2007 Apr 13;282(15):11590-601.
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P.
Regulation of NMDA receptor trafficking by amyloid-beta.
Nat Neurosci. 2005 Aug;8(8):1051-8.