It's of interest that mRNA levels of the calcineurin inhibitor, DSCR1, are also much higher in AD brain (1). The recent study be Lee and colleagues finds that DSCR1 interacts with Tollip and positively modulates IL-1R signalling (2). Tollip is an IRAK-1 inhibitor. This would seem to suggest problems with TLR2/TLR4 signalling in AD. This is supported by the Landreth study finding that CD14 and TLR2 and TLR4 bind Aβ to stimulate microglial activation (3). The KEGG link is below for the TOLL RECEPTOR signaling pathway (4).

References:
1. Ermak G, Morgan TE, Davies KJ. Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. J Biol Chem. 2001 Oct 19;276(42):38787-94. Abstract

2. Lee JY, Lee HJ, Lee EJ, Jang SH, Kim H, Yoon JH, Chung KC. Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling. Biochim Biophys Acta. 2009 Dec;1790(12):1673-80. Abstract

3. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. 2009 Sep 23;29(38):11982-92. Abstract

4. Toll-like receptor signaling pathway—Homo sapiens (human)

View all comments by Mary Reid

The connection between DSCR1 and calcineurin/NFAT signaling with AD is indeed interesting. It’s clear that NFATs help increase DSCR1 expression in several different cell types (e.g., 1,2). Elevated DSCR1 levels in AD tissue are therefore consistent with recent reports showing increased calcineurin/NFAT activation during AD (3,4). It’s also clear that DSCR1 interacts directly with calcineurin, but DSCR1 is not a simple calcineurin inhibitor. In fact, DSCR1 can exert permissive effects on calcineurin activity depending on the presence and activation levels of other accessory proteins (5). DSCR1 may, therefore, help attenuate or drive calcineurin/NFAT signaling within AD through negative or positive feedback loops.

References:
1. Yang, J., Rothermel, B., Vega, R. B., Frey, N., McKinsey, T. A., Olson, E. N., Bassel-Duby, R., and Williams, R. S. (2000) Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ.Res. 87, E61-68. Abstract

2. Canellada A, Ramirez BG, Minami T, Redondo JM, Cano E (2008) Calcium/calcineurin signaling in primary cortical astrocyte cultures: Rcan1-4 and cyclooxygenase-2 as NFAT target genes. Glia. 56:709-22. Abstract

3. Abdul MH, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, Patel ES, Baig I, Levine, H III, Murphy MP, Kraner SD, Norris CM (2009) Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. The Journal of Neuroscience 29:12957-12969. Abstract

4. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT (2010) Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 30:2636-49. Abstract

5. Liu Q, Busby JC, Molkentin JD (2009) Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point. Nat Cell Biol 11:154-61. Abstract

View all comments by Chris Norris

I certainly like the idea that this season might go down in the Alzheimer research history as the summer of calcium, with four major studies recently forging new links between calcium problems in neurons and Alzheimer disease (AD). However, a major issue is how AD-related, deranged calcium signals lead to neuron dysfunction and death.

We have shown a few days ago (Sanz-Blasco et al., 2008) that Aβ oligomers (but not fibrils) promote Ca2+ influx into primary neurons (but not glia). This influx is followed by mitochondrial calcium overload as monitored by photon counting imaging of low-affinity aequorin targeted to mitochondria. The relevance of this finding is that prevention of mitochondrial calcium overload using low concentrations of mitochondrial uncoupler protects neurons against Aβ-induced ROS production, permeability transition, cytochrome c release, and apoptosis and cell death.

Moreover, we found that a series of carboxylic, non-steroidal anti-inflammatory drugs including R-flurbiprofen prevent the mitochondrial calcium overload, acting as mitochondrial...  Read more

I certainly like the idea that this season might go down in the Alzheimer research history as the summer of calcium, with four major studies recently forging new links between calcium problems in neurons and Alzheimer disease (AD). However, a major issue is how AD-related, deranged calcium signals lead to neuron dysfunction and death.

We have shown a few days ago (Sanz-Blasco et al., 2008) that Aβ oligomers (but not fibrils) promote Ca2+ influx into primary neurons (but not glia). This influx is followed by mitochondrial calcium overload as monitored by photon counting imaging of low-affinity aequorin targeted to mitochondria. The relevance of this finding is that prevention of mitochondrial calcium overload using low concentrations of mitochondrial uncoupler protects neurons against Aβ-induced ROS production, permeability transition, cytochrome c release, and apoptosis and cell death.

Moreover, we found that a series of carboxylic, non-steroidal anti-inflammatory drugs including R-flurbiprofen prevent the mitochondrial calcium overload, acting as mitochondrial uncouplers and protecting against cell death. These effects are achieved at NSAID concentrations in the low microM range, well below the range required for targeting γ-secretase. Therefore, mitochondrial calcium overload contributes to cell death induced by Aβ oligomers.

In addition, the long-debated mechanism of neuroprotection by NSAIDs could be related to the calcium hypothesis of Alzheimer disease rather than to their ability to target inflammation or secretases. Whether mitochondrial calcium overload is also involved in cell death induced by excess calcium release promoted by either loss of ER calcium leak or IP3 receptor modulation remains to be established.

References:
Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L. Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS ONE. 2008 Jul 23;3(7):e2718. Abstract

View all comments by Carlos Villalobos

One of the salient outcomes that could reshape our thinking about the role of astrocytes in AD is that calcium signaling alterations linked to dense-core plaque deposits extend beyond the spatial domain of the discrete histopathology, and can synchronize larger populations of astrocyte and astrocyte circuits, either through extracellular signaling or gap junctions. What that calcium is doing, its originating source, and how it affects neurophysiology has yet to be determined in these models.

Certainly, a strength of this study is the confirmation of cell type, as previous in-vivo studies have not done so with certainty and were claiming changes in neuronal calcium signaling, and may have largely been observing astrocytes or other cell types. A potential overinterpretation in this study is relying only on methoxy-X04 staining as an indicator of plaque presence, as this only stains insoluble, late-stage, dense-core deposits and not other perhaps more pathogenic forms such as oligomers and other soluble β amyloid species. In addition, it would be quite interesting to...  Read more

One of the salient outcomes that could reshape our thinking about the role of astrocytes in AD is that calcium signaling alterations linked to dense-core plaque deposits extend beyond the spatial domain of the discrete histopathology, and can synchronize larger populations of astrocyte and astrocyte circuits, either through extracellular signaling or gap junctions. What that calcium is doing, its originating source, and how it affects neurophysiology has yet to be determined in these models.

Certainly, a strength of this study is the confirmation of cell type, as previous in-vivo studies have not done so with certainty and were claiming changes in neuronal calcium signaling, and may have largely been observing astrocytes or other cell types. A potential overinterpretation in this study is relying only on methoxy-X04 staining as an indicator of plaque presence, as this only stains insoluble, late-stage, dense-core deposits and not other perhaps more pathogenic forms such as oligomers and other soluble β amyloid species. In addition, it would be quite interesting to compare calcium signaling differences between the APP and APP/PS1 mice.

View all comments by Grace (Beth) Stutzmann

This may be a naive question, but if amyloid deposition in the brain is a critical factor in AD-related behavioral sequelae, why is it so difficult to induce a behavioral modification of statistical relevance following Aβ vaccination, since reports show a strong amyloid plaque clearance effect?

View all comments by Elliott Mufson

I think another model for this kind of study (after parabiotics and vampires) could be pregnant mice. The placental barrier between mother and fetus highly leaky, allowing the passage of, for instance, maternal antibodies (mainly IgG). It seems to me that there is a general observation that the maternal organism appears 'rejuvenated' during pregnancy.

View all comments by Ivan Goussakov

We have recently observed that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses (Garcia-Marin et al., 2009). Indeed, a large proportion of plaques are in contact with neurons, and of the several hundred neurons that we found to come into contact with plaques, in no cases were perisomatic terminals found at the surface of the neuron that was directly touching the plaque. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These findings are consistent with the in-vivo calcium-imaging experiments of Busche et al. (2008).

References:
Busche, M.A., Eichhoff, G., Adelsberger, H., Abramowski, D., Wiederhold, K.H., Haass, C., Staufenbiel, M., Konnerth, A., and Garaschuk, O. (2008). Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science 321, 1686-1689. Abstract

Garcia-Marin V, Blazquez-Llorca L, Rodriguez J, Boluda S, Muntane G, Ferrer I and DeFelipe J (2009) Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques. Front. Neuroanat. 3:28. Abstract

View all comments by Javier DeFelipe