Scientists know that some familial AD mutations cause a toxic flood of calcium to enter neurons, but they know much less about how that calcium does its dirty work. In the Jul 22 Proceedings of the National Academy of Sciences, researchers led by Kevin Foskett at the University of Pennsylvania, Philadelphia, shed some light on these downstream pathways. They found that calcium constitutively activates the transcription factor cAMP response element binding protein (CREB), well known for its role in promoting learning and memory. Foskett and colleagues link overactive CREB to increased cell death in vitro, suggesting that, while a little CREB activity may be good for your brain, perhaps too much is bad.

Kim Green at the University of California, Irvine, praised the study, noting that “for years we have been talking about how these presenilin mutations, and perhaps presenilin itself, modulates calcium, but we have never really looked at the consequences of those calcium changes.” He was not involved in the work.

Numerous previous studies have shown that familial AD presenilin-1 (PS1) mutations result in exaggerated calcium release from internal cellular stores, although researchers disagree about the exact mechanism (see, e.g., Stutzmann et al., 2006; Stutzmann et al., 2007; Bezprozvanny et al., 2008; ARF related news story on Green et al., 2008; ARF related news story on Green and LaFerla, 2008; see also ARF live discussion). Previous work by Foskett and colleagues linked the inositol 1,4,5-triphosphate receptor (InsP3R) to PS1-induced calcium release (see ARF related news story).

First author Marioly Müller wanted to look more closely at cellular events driven by calcium toxicity. She used cultured neural cell lines in which she expressed either wild-type or mutant PS1. Cells containing the familial M146L PS1 mutation, but not those with wild-type PS1, had large spontaneous calcium spikes, which the researchers abolished by blocking InsP3R either pharmacologically or with short interfering RNA. Looking downstream, Müller and colleagues found that cells with mutant presenilin also contained more activated CREB, which accumulated in the nucleus. The researchers could block CREB activation by either knocking down mutant PS1 or inhibiting InsP3R.

The authors went on to dissect the pathway by which excess calcium turned on CREB, finding that it involved activation of Ca2+/CaM kinase kinase β (CaMKKβ) and Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Müller and colleagues also linked the pathway to cell death in vitro, finding that cells with mutant PS1 died in fivefold greater numbers and were more sensitive to the toxic effects of Aβ than cells with wild-type PS1. Inhibiting InsP3R, CaMK, or CREB returned cell death to normal levels.

To extend these results in vivo, the authors used the triple-transgenic 3xTgAD mouse, which expresses the M146V PS1 mutation. At four to six weeks of age, before these mice show any amyloid or tau deposition, or any cognitive deficits, they had a three- to fivefold increase in activated CaMKIV and CREB, as well as in several genes turned on by CREB. A mouse that carried only the M146V mutation gave similar results.

Because inhibiting CREB reduced cell death to normal levels in vitro, the authors suggest that constitutively active CREB might play a role in cell death in familial AD. This idea runs a bit against the grain: CREB activation is usually considered beneficial, as many studies have touted its importance for learning and memory (see, e.g., ARF related conference story; ARF news story; and ARF related news story). CREB levels are typically down in AD brains (see, e.g., Saura and Valero, 2011 and ARF related news story on Caccamo et al., 2010). Increasing CREB improves memory and protects synapses in AD models (see ARF related news story on Gong et al., 2004).

What explains this discrepancy? One difference, the authors suggest, is that constitutive CREB activity could be an early feature that precedes Aβ pathology, while lowered CREB levels are a consequence of amyloid accumulation and occur much later. Another factor is the chronic nature of the activation. Other studies have found harmful effects, such as memory problems, cognitive deficits, and neurodegeneration, from continuous CREB activity (see Ramos et al., 2003; Lopez de Armentia et al., 2007; and Viosca et al., 2009). Some of the genes that CREB turns on, such as c-fos and nitric oxide synthase, also cause cell degeneration when expressed too highly, the authors note.

However, Green pointed out that the young PS1 mutant mice have no cognitive problems or neurodegeneration, despite their elevated CREB. People with mutant PS1 also show no difficulties for the first several decades of life, implying that if CREB is overactive in the human brain, it is not immediately harmful. Perhaps excess CREB activity has no effect on cognition, or even helps to offset the negative effects of too much calcium, Green suggested. Another factor to keep in mind, Green said, is that presenilin mutations are found in only a small fraction of AD cases. This study “does not tell us anything about sporadic AD,” he noted, particularly as wild-type presenilin did not have a pathological effect in these studies. One of the next questions to be answered, Green told ARF, is whether the effect of mutant presenilin on calcium and CREB is also a physiological role of presenilins in normal tissues, which would make these results more broadly applicable to AD.—Madolyn Bowman Rogers

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Comments on News and Primary Papers

  1. The prominence of early/pre-symptomatic calcium signaling disruptions in mutant presenilin (PS)-expressing neurons has been well established in the AD field, but to fortify relevance to the disease process, dysregulated calcium still needs to be transduced into a pathogenic mechanism. This study by Müller et al. is very effective at demonstrating how increased ER calcium release, via the IP3R, results in constitutive upregulation of a calcium-regulated kinase and gene transcription pathway.

    Normally, CaMKIV and pCREB activation are associated with neuronal functionality and plasticity, and are recruited in a specific and activity-dependent manner. However, with mutant PS expression, this signaling cascade and associated immediate early genes are continuously engaged. While there are many long-term negative effects that can stem from this homeostasis shift (such as the demonstrated increased vulnerability to cell death and amyloid toxicity), the specific links to AD pathology are still to be determined.

    We know that at early disease stages, prior to the onset of amyloid pathology or cognitive impairment, these neurons "appear" normal from an electrophysiological and synaptic transmission standpoint, despite a "below the radar" shift in calcium release and intracellular signaling homeostasis. It is likely that sustained dyshomeostasis of normally functional pathways can ultimately contribute to dysfunctional outcomes.

    Studies such as these stress the importance of investigating early pathogenic mechanisms in AD. By targeting proximal and reversible aberrant signaling cascades, these approaches will likely provide the greatest opportunity for generating preventative or disease-altering therapeutics.

    View all comments by Grace Stutzmann

References

News Citations

  1. Pump It Up—Presenilins Linked to ER SERCA Activity
  2. More Calcium News: Plaques Cause Dendrite Damage via Ion Overload
  3. Channel Surfing—Two Studies Strengthen Calcium-AD Connection
  4. Copper Mountain: Can CREB Save Memory?
  5. Mechanisms and Memory: The Choreography of CREB, the Balance of BDNF
  6. Enhancing Old Memory Pathways Through New Tricks
  7. Sharpen Your Synapses with Rolipram!

Webinar Citations

  1. Calcium in AD Pathogenesis

Paper Citations

  1. . Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer's disease mice. J Neurosci. 2006 May 10;26(19):5180-9. PubMed.
  2. . Enhanced ryanodine-mediated calcium release in mutant PS1-expressing Alzheimer's mouse models. Ann N Y Acad Sci. 2007 Feb;1097:265-77. PubMed.
  3. . Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 2008 Sep;31(9):454-63. PubMed.
  4. . SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol. 2008 Jun 30;181(7):1107-16. PubMed.
  5. . Linking calcium to Abeta and Alzheimer's disease. Neuron. 2008 Jul 31;59(2):190-4. PubMed.
  6. . The role of CREB signaling in Alzheimer's disease and other cognitive disorders. Rev Neurosci. 2011;22(2):153-69. PubMed.
  7. . CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22687-92. PubMed.
  8. . Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest. 2004 Dec;114(11):1624-34. PubMed.
  9. . Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron. 2003 Nov 13;40(4):835-45. PubMed.
  10. . cAMP response element-binding protein-mediated gene expression increases the intrinsic excitability of CA1 pyramidal neurons. J Neurosci. 2007 Dec 12;27(50):13909-18. PubMed.
  11. . Chronic enhancement of CREB activity in the hippocampus interferes with the retrieval of spatial information. Learn Mem. 2009 Mar;16(3):198-209. PubMed.

Other Citations

  1. 3xTgAD mouse

Further Reading

Primary Papers

  1. . Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13293-8. PubMed.