Among cell types on the neuroscience stage, neurons appear front and center, garnering most of the research attention. However, scientists, like theater critics, are coming to recognize that a show relies just as much on supporting characters as on lead actors. With this realization, a batch of new studies shifts the spotlight from neurons to astrocytes, revealing critical roles for these helper cells in Parkinson and Alzheimer diseases and in processes as fundamental as sleep and circadian rhythm.

Astrocytes outnumber neurons in the human brain, and research suggests that problems with these star-shaped glial cells may underlie the massive cell death in various neurodegenerative diseases. “These sick astrocytes can no longer support the neurons and, even though they themselves may not die, their inability to provide neurons with critical components for function and survival leads to the death of the neuron,” explained Jeffrey Johnson at the University of Wisconsin, Madison, in an e-mail to ARF. “Finding ways to fix these sick astrocytes may yield great benefit in multiple neurodegenerative diseases.”

One feature shared by many neurodegenerative conditions is oxidative stress. Nuclear erythroid 2-related factor 2 (Nrf2) presumably helps neurons fight this damage by binding a DNA sequence known as the antioxidant response element (ARE) to ramp up expression of protective genes. Several months ago, Johnson and colleagues reported that targeting Nrf2 overexpression to astrocytes delayed motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis (see ARF related news story).

In this week’s PNAS Early Edition, a Johnson-led team shows that a similar strategy works in the MPTP mouse model for Parkinson disease. (MPTP, or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is a toxin that kills dopamine-producing cells in the substantia nigra, mimicking PD pathology.) Lead author Pei-Chun Chen and colleagues began by examining the role of Nrf2 in MPTP-induced toxicity. Toward this end, they engineered mice that expressed a reporter gene (human placental alkaline phosphatase) under the control of the ARE promoter. In these mice, MPTP treatment increased reporter activity in the substantia nigra, consistent with Nrf2-mediated activation of protective genes in that PD-affected region. Nrf2 knockout mice showed increased sensitivity to the toxin, compared with wild-type animals. Conversely, MPTP-mediated neuronal death disappeared in transgenic mice that overexpressed Nrf2—even when expression of the gene was restricted to astrocytes (by putting into Nrf2 knockout mice a Nrf2 transgene driven by an astrocyte-specific promoter).

“These data strongly suggest that finding ways to boost the level of Nrf2 activation in human brain should have significant impact on PD development and progression,” Johnson told ARF via e-mail. Postmortem brain tissue from Parkinson’s patients shows enhanced expression of several ARE-driven genes (NAD(P)H:quinone oxidoreductase 1and heme oxygenase-1), supporting the potential importance of Nrf2-ARE signaling in PD. (The therapeutic potential of this pathway is reviewed in Calkins et al., 2008.) Johnson’s team is currently investigating the involvement of astrocytic Nrf2 in Huntington and Alzheimer diseases.

Meanwhile, new research by Donna Wilcock, Mike Vitek, and Carol Colton at Duke University Medical Center, Durham, North Carolina, links astrocytes with disease from a different angle. In four AD mouse models with varying vascular amyloid load and disease severity (APPSwe, APPSwDI [Davis et al., 2004], APPSw/NOS2-/- [Colton et al., 2006], and APPSwDI/NOS2-/- [Wilcock et al., 2008]), the researchers found that vascular Aβ disrupted astrocyte-vessel connections and resulted in loss of astrocytic water (aquaporin 4) and potassium (Kir4.1 and BK) channels. Correlating with vascular Aβ load, the AD mice also showed decreased levels of an anchoring protein (dystrophin 1) common to these channels. In addition, aquaporin 4, Kir4.1, and dystrophin 1 were reduced in autopsied brain tissue from AD patients with moderate to severe vascular amyloid deposition (i.e., CAA, or cerebral amyloid angiopathy). The findings appeared online 19 January in the journal Neuroscience.

“Overall, these data suggest that CAA can result in more extensive damage than simply at the vasculature,” lead author Wilcock wrote in an e-mail to ARF. “By losing these potassium and water channels, it is likely that neuronal membrane potentials, and therefore excitability, are altered.” She speculates that these changes could lead to seizures, changes in long-term potentiation and long-term depression (the processes in which synapses are strengthened and weakened, respectively), and ultimately, neurodegeneration. Ongoing studies in the AD mice should help tease out these possibilities, Wilcock noted.

Interestingly, the Duke scientists found reduced levels of the astroglial gap junction protein connexin 43 in AD mice compared with wild-type controls. In a separate study published in the 5 December Science, researchers led by Christian Giaume at INSERM, Paris, report that connexins 43 and 30 are required to assemble astrocytes into metabolic networks that feed neurons with lactate, their preferred energy source (see ARF related news story). Using fluorescent glucose derivatives to track nutrients in astroglial networks from mouse hippocampus, first author Nathalie Rouach and colleagues showed that nutrient trafficking was halved in connexin 43 knockouts, reduced by a third in connexin 30-deficient mice, and completely wiped out in double-knockout mice. The findings offer a molecular explanation for how astrocytes may play such key roles in neural transmission, disease, and other energy-taxing situations. This trafficking could be induced by stimulating Schaeffer collateral pathways in hippocampal slices, suggesting a connection with electrical activity. Remarkably, depression of synaptic transmission induced by glucose deprivation could be reversed by adding glucose via patch pipette to a single astrocyte 77 μM from the recording electrode, suggesting the nutrient networking offers broad neural support.

This work may change the way researchers think of astrocytes, long regarded as single entities. That view drew support from a recent study suggesting that astrocytes in the ferret visual cortex respond to stimuli as individual cells with unique response patterns (see ARF related news story). But when it comes to keeping neurons well nourished, the new data suggest that a team approach may work best. The authors propose that “supply of energetic metabolites involves groups of connected astrocytes to reach more efficiently and distally the sites of high neuronal demand.”

And if poring through all these studies has left you bleary-eyed, better guess which cells you should blame. In the 29 January issue of Neuron, researchers led by Philip Haydon, Tufts University, Boston, and Marcos Frank, University of Pennsylvania, Philadelphia, report that astrocytes help bring on the urge to sleep and mediate cognitive losses that come with inadequate shuteye.

What led the authors to suspect that astrocytes might regulate sleep in the first place? Previous work had identified adenosine as a chemical mediator that promotes sleep after long wakeful periods (Porkka-Heiskanen et al., 1997). Since adenosine is transmitted between cells through SNARE complexes—structures formed to facilitate exocytotic release of chemical messengers by glial cells—the researchers pegged astrocytes as a prime candidate for mediating adenosine’s effects on sleep.

To test this idea, first author Michael Halassa, also at the University of Pennsylvania, and colleagues used mice in which astrocyte-derived adenosine could be blocked by conditional expression of a dominant-negative SNARE (dnSNARE) transgene selectively in astrocytes (Pascual et al., 2005). After depriving the mice of sleep for short periods, they assessed their urge to sleep, termed sleep pressure, using electroencephalography (EEG) to measure patterns of brain electrical activity. With these readouts, Halassa and colleagues found reduced sleep pressure in mice where dnSNARE was turned on in astrocytes. Furthermore, in these animals, performance on a memory test was unaffected by a sleep deprivation regimen that weakens wild-type animals’ memory. Pharmacological inhibition of adenosine transmission produced similar effects—but only when the drugs targeted adenosine receptors of the A1 type.

“Taken together, these studies provide the first demonstration that a nonneuronal cell type of the brain, the astrocyte, modulates behavior….” the authors write. “Given that astrocytes express novel receptors, these glial cells offer a novel target for the development of therapeutics for sleep and cognitive disorders.” This could have relevance for neurodegenerative disease. For instance, some AD patients have disturbed sleep and circadian patterns, and a recent study suggests that restoring the body’s natural circadian rhythm could improve some mood-related and cognitive AD symptoms (see ARF related news story).

Along these lines, researchers led by Frank Scheer at Harvard Medical School, Boston, provide further evidence of circadian failure in aging and AD. In their study published this week in PNAS Early Edition, first author Kun Hu and colleagues show that certain circadian patterns of motor activity fade in seniors and in AD patients. The effects resemble those seen in animals whose master circadian pacemaker (i.e., the SCN, or suprachiasmatic nucleus) has been removed. If subsequent studies can nail down the SCN as a crucial mediator of these circadian losses, treatments that improve SCN function might hold promise for relieving some of the sleep-wake rhythm disturbances in AD.—Esther Landhuis.

References:
Chen P-C, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte. 2009 February. PNAS Early Edition. Abstract

Wilcock DM, Vitek MP, Colton CA. Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease. Neuroscience. 19 January 2009. Abstract

Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science. 2008 Dec 5;322(5907):1551-5. Abstract

Halassa MM, Florian C, Fellin T, Munoz JR, Lee S-Y, Abel T, Haydon PG, Frank MG Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss. Neuron. 2009 Jan 29;61(2):213-9 Abstract

Hu K, Van Someren EJW, Shea SA, Scheer FA. Reduction of scale-invariance of activity fluctuations with aging and Alzheimer’s disease: Involvement of the circadian pacemaker. 2009 February. PNAS Early Edition. Abstract

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  1. A novel mechanism is described through which activity acts on the neurovascular unit to promote synaptic transmission.

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References

News Citations

  1. Nrf2 Pumps Up Astrocyte Protection of Motor Neurons in ALS Model
  2. The Lactic Acid Shuttle—It May Change How We Image the Brain
  3. Research Brief: Ferreting Out the Role of Astrocytes in the Brain
  4. Research Brief: Beefing Up Circadian Rhythm Helps AD Symptoms

Paper Citations

  1. . The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009 Mar;11(3):497-508. PubMed.
  2. . Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004 May 7;279(19):20296-306. PubMed.
  3. . NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12867-72. PubMed.
  4. . Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci. 2008 Feb 13;28(7):1537-45. PubMed.
  5. . Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science. 1997 May 23;276(5316):1265-8. PubMed.
  6. . Astrocytic purinergic signaling coordinates synaptic networks. Science. 2005 Oct 7;310(5745):113-6. PubMed.
  7. . Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2933-8. PubMed.
  8. . Astroglial metabolic networks sustain hippocampal synaptic transmission. Science. 2008 Dec 5;322(5907):1551-5. PubMed.
  9. . Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron. 2009 Jan 29;61(2):213-9. PubMed.
  10. . Reduction of scale invariance of activity fluctuations with aging and Alzheimer's disease: Involvement of the circadian pacemaker. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2490-4. PubMed.

Other Citations

  1. APPSwe

External Citations

  1. Abstract

Further Reading

Papers

  1. . The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009 Mar;11(3):497-508. PubMed.
  2. . Astroglial metabolic networks sustain hippocampal synaptic transmission. Science. 2008 Dec 5;322(5907):1551-5. PubMed.
  3. . Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron. 2009 Jan 29;61(2):213-9. PubMed.
  4. . Reduction of scale invariance of activity fluctuations with aging and Alzheimer's disease: Involvement of the circadian pacemaker. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2490-4. PubMed.
  5. . Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2933-8. PubMed.

News

  1. Nrf2 Pumps Up Astrocyte Protection of Motor Neurons in ALS Model
  2. Research Brief: Beefing Up Circadian Rhythm Helps AD Symptoms
  3. The Lactic Acid Shuttle—It May Change How We Image the Brain
  4. Research Brief: Ferreting Out the Role of Astrocytes in the Brain

Primary Papers

  1. . Astroglial metabolic networks sustain hippocampal synaptic transmission. Science. 2008 Dec 5;322(5907):1551-5. PubMed.
  2. . Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron. 2009 Jan 29;61(2):213-9. PubMed.
  3. . Reduction of scale invariance of activity fluctuations with aging and Alzheimer's disease: Involvement of the circadian pacemaker. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2490-4. PubMed.
  4. . Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2933-8. PubMed.