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

Anti-inflammatories for AD—Time for Consideration of the Next Generation?
This news article, discussing the impressive results reported by Yasumasa Yoshiyama, Virginia Lee, John Trojanowski, and their colleagues from the University of Pennsylvania, is most timely, and its importance should not be underestimated by the Alzheimer research community. For it represents now yet another new approach to AD that utilizes a potent and novel anti-inflammatory and reports rather startlingly positive, if preliminary, data.

This approach, using the macrolactam immunosuppressive FK506, joins the promising preliminary results reported by Dodel and his colleagues in Bonn [1], by Norman Relkin and his colleagues from Weill-Cornell using IVIG [2], and our pilot results using perispinal etanercept [3] in suggesting that the use of novel and biologic anti-inflammatories may merit serious consideration for further investigation as primary AD therapeutics.

The Penn group’s findings of early synaptic dysfunction are congruous with increasing evidence linking TNFα and...  Read more

Anti-inflammatories for AD—Time for Consideration of the Next Generation?
This news article, discussing the impressive results reported by Yasumasa Yoshiyama, Virginia Lee, John Trojanowski, and their colleagues from the University of Pennsylvania, is most timely, and its importance should not be underestimated by the Alzheimer research community. For it represents now yet another new approach to AD that utilizes a potent and novel anti-inflammatory and reports rather startlingly positive, if preliminary, data.

This approach, using the macrolactam immunosuppressive FK506, joins the promising preliminary results reported by Dodel and his colleagues in Bonn [1], by Norman Relkin and his colleagues from Weill-Cornell using IVIG [2], and our pilot results using perispinal etanercept [3] in suggesting that the use of novel and biologic anti-inflammatories may merit serious consideration for further investigation as primary AD therapeutics.

The Penn group’s findings of early synaptic dysfunction are congruous with increasing evidence linking TNFα and other inflammatory mechanisms with synaptic dysfunction in AD [4-12]. My own findings of rapid improvement, within minutes, in verbal fluency, affect, and attention following perispinal etanercept [3,13] (some results as yet unpublished) are perhaps best explained by the known effects of TNFα on synaptic transmission and synaptic scaling [14-18].

Taken together, all of the above constitute support for the Penn group’s conclusion in their new article that “it is plausible that neurodegenerative tauopathies could be ameliorated by pharmacologic modulation of neuroinflammation.”

It is most unfortunate that publication of this important new paper by the group at Penn should coincide with the untimely passing of Leon Thal, one of the legendary figures in Alzheimer research. Perhaps it may be of some comfort that Dr. Thal performed some of the seminal early research investigating pharmacologic anti-inflammatory approaches to AD [19-21]. If Lee and colleagues’ new clues to the potential efficacy of these next-generation anti-inflammatories survive the rigors of testing in randomized, controlled trials, then we will all owe an additional debt of gratitude to the efforts of those who started the AD research community looking in this direction.

References
1. Dodel RC, Du Y, Depboylu C, Hampel H, Frolich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nolker C, Moller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1472-4. Abstract

2. McCaffrey P. Pilot Study Shows Promise of Passive Immunotherapy. Alzheimer Research Forum, April 14, 2005. See ARF related news story

3. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006 Apr 26;8(2):25. Abstract

4. Albensi BC, Mattson MP. Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse. 2000 Feb;35(2):151-9. Abstract

5. Small DH, Mok SS, Bornstein JC. Alzheimer's disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci. 2001 Aug;2(8):595-8. Review. No abstract available. Abstract

6. Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22;295(5563):2282-5. Abstract

7. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. Abstract

8. LaFerla FM, Oddo S. Alzheimer's disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. Review. Abstract

9. Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005 Mar 23;25(12):3219-28. Erratum in: J Neurosci. 2005 Jun 1;25(22):1 p following 5454. Abstract

10. Bell KF, Claudio Cuello A. Altered synaptic function in Alzheimer's disease. Eur J Pharmacol. 2006 Sep 1;545(1):11-21. Epub 2006 Jun 27. Review. Abstract

11. Puzzo D, Palmeri A, Arancio O. Involvement of the nitric oxide pathway in synaptic dysfunction following amyloid elevation in Alzheimer's disease. Rev Neurosci. 2006;17(5):497-523. Review. Abstract

12. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. Epub 2006 Mar 19. Abstract

13. Tobinick E, Shirinyan D, Gross H. TNF Modulation for Treatment of Alzheimer's Disease: Effects on Verbal Function. Abstract presented at the Days of Molecular Medicine Conference, Karolinska Institutet, Stockholm, Sweden, May 27, 2006.

14. Pickering M, Cumiskey D, O'Connor JJ. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol. 2005 Sep;90(5):663-70. Epub 2005 Jun 8. Review. Abstract

15. Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature. 1998 Feb 26;391(6670):892-6. Abstract

16. Watt AJ, van Rossum MC, MacLeod KM, Nelson SB, Turrigiano GG. Activity coregulates quantal AMPA and NMDA currents at neocortical synapses. Neuron. 2000 Jun;26(3):659-70. Abstract

17. Rosenberg PB. Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatry. 2005 Dec;17(6):503-14. Review. Abstract

18. Rosenberg PB. Editorial: cytokine inhibition for treatment of Alzheimer's disease. MedGenMed. 2006 Apr 26;8(2):24. No abstract available. Abstract

19. Grundman M, Corey-Bloom J, Thal LJ. Perspectives in clinical Alzheimer's disease research and the development of antidementia drugs. J Neural Transm Suppl. 1998;53:255-75. Review. Abstract

20. Thal LJ. Anti-inflammatory drugs and Alzheimer's disease. Neurobiol Aging. 2000 May-Jun;21(3):449-50; discussion 451-3. No abstract available. Abstract

21. Thal LJ. Therapeutics and mild cognitive impairment: current status and future directions. Alzheimer Dis Assoc Disord. 2003 Apr-Jun;17 Suppl 2:S69-71. Review. No abstract available. Abstract

View all comments by Edward Tobinick

Walton's recent study of pyramidal neurons from the hippocampus of autopsy-confirmed AD patients found that all NFTs were associated with cytoplasmic aluminum. While the absorption of the metal by the NFTs may reduce inflammation and oxidation, NFT density ultimately killed neurons by enucleation (1). Formation of NFTs will also impede the flow of tau, building materials and chemicals through the axons as a number of authors have explored. Transport deficits take place early in AD. Clogging of axonal communication between the entorhinal cortex with its high aluminum level in AD, and the hippocampus could be one source of isolation of the hippocampus (2,3).

References:
1. Walton JR. Aluminum in hippocampal neurons from humans with Alzheimer's disease. Neurotoxicology 2006; 27:385-394. Abstract

2. Singer SM, Chambers CB, Newfry GA, Norlund MA, Muma NA. Tau in aluminum-induced neurofibrillary tangles. Neurotoxicology 1997; 18(1): 63-76. Abstract

3. Andrasi E, Pali N, Molnar Z, Kosel S. Brain aluminum, magnesium and phosphorous contents of control and Alzheimer-diseased patients. J Alzheimers Dis 2005; 7: 273-284. Abstract

View all comments by Erik Jansson

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

Overall, the data now show that loss of neuronal glutamate release leads to downregulation of glutamate transporters in astrocytes. This makes a lot of sense for a homeostatic mechanism. It implies that the previously noted downregulation of astrocyte glt1 was a consequence of the neurodegenerative process rather than necessarily being part of the disease process. Drugs like riluzole have had only weak effects and conceivably their actions could relate to some other effect of this drug rather than any effect on glutamate transport.

The drug resistance problem caused by upregulation of P-glycoprotein at the blood-brain barrier is well documented and comes as no surprise. Getting drugs across the CNS is a big problem. The current findings showing that glial downregulation of glt1 is caused by loss of neurons suggest that even if high riluzole levels could be maintained in the CNS, this still would not be much more helpful for treating ALS. Many other genes are likely to turn off or on in astrocytes as a result of neuron degeneration and quite possibly these will turn out to be...  Read more

Overall, the data now show that loss of neuronal glutamate release leads to downregulation of glutamate transporters in astrocytes. This makes a lot of sense for a homeostatic mechanism. It implies that the previously noted downregulation of astrocyte glt1 was a consequence of the neurodegenerative process rather than necessarily being part of the disease process. Drugs like riluzole have had only weak effects and conceivably their actions could relate to some other effect of this drug rather than any effect on glutamate transport.

The drug resistance problem caused by upregulation of P-glycoprotein at the blood-brain barrier is well documented and comes as no surprise. Getting drugs across the CNS is a big problem. The current findings showing that glial downregulation of glt1 is caused by loss of neurons suggest that even if high riluzole levels could be maintained in the CNS, this still would not be much more helpful for treating ALS. Many other genes are likely to turn off or on in astrocytes as a result of neuron degeneration and quite possibly these will turn out to be more relevant.

View all comments by Ben Barres

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