Summary

Ben Barres led the first in a series of Alzforum discussions about the role of glial cells in Alzheimer’s and other neurodegenerative diseases. It has become trendy to say that glia are more than just glue, but in reality, science has not yet advanced significantly from the days when glial cells were summarily dismissed as dull support cells for neurons.

Why do we know so little about the function of these cells in health and neurodegeneration? What are the salient questions to be tackled today? What does it take to move the neurodegeneration field to make serious inroads into the issue? Read Barres’ lucid backgrounder below and send your comments to Gabrielle@alzforum.org.

Ben Barres led this live discussion on 20 October 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:
Participants: Ben Barres (Stanford University), June Kinoshita (Alzheimer Research Forum), Gabrielle Strobel (Alzheimer Research Forum), Wenan Qiang (Northwestern University), Linda Van Eldik (Northwestern University), Chiara Cupidi (University of Verona, Italy).

Ben Barres
Hi, June!

June Kinoshita
Hi, everyone!

Wenan Qiang
I'm Wenan Qiang; I work at Linda Van Eldik's lab.

Ben Barres
Hi, Wenan; what do you work on?

Wenan Qiang
I am working on glia inflammation.

Ben Barres
That's great!

Linda Van Eldik
Hi, everyone.

Ben Barres
Linda, do you work on AD? Wenan, do you mean microglia or reactive astrocytes?

Gabrielle Strobel
Could everyone identify themselves briefly as we begin, so we all know who's here. I am Gabrielle Strobel, managing editor of the Alzforum.

June Kinoshita
June Kinoshita, executive editor of Alzforum.

Ben Barres
Hi, I’m Ben Barres; I am a neurobiologist at Stanford interested in neuron-glial interactions.

Linda Van Eldik
Linda Van Eldik, Northwestern University, co-director of the Center for Drug Discovery and Chemical Biology, associate director of the Northwestern Alzheimer's Disease Center, studying mechanisms of glial activation and the potential of targeting chronic glial activation for AD therapeutics.

Chiara Cupidi
I'm Chiara Cupidi; I work at University of Verona, Italy.

Gabrielle Strobel
Ben, Linda does beautiful work on glial inflammation and the role of ApoE, among other players, in that. Ben, do you think aging is the strongest risk factor for late-onset AD because of the astrogliosis observed in the aging brain?

Ben Barres
Great question! I have read that with aging some neurons are slowly dying, just from old age, and anytime neurons die, reactive gliosis seems to occur. So there definitely is probably more reactive gliosis with aging.

Gabrielle Strobel
Tuck Finch has data on that showing correlates with some performance drops in aging, but for AD I wonder if astrogliosis could make the brain more vulnerable to other insults?

Ben Barres
Gabrielle, yes, it's another great question. What is the point of astrocytes being reactive—is it good or bad? Perhaps it could be reversed, but maybe that would have adverse consequences. For instance, Mike Sofroniew showed that reactive astrocytes are important in sealing up the blood-brain barrier (BBB) after brain injury (see Bush et al., 1999).

Gabrielle Strobel
And I believe Tony Wyss-Coray has data on active astrocytes taking up amyloid (see ARF related news story).

Ben Barres
Do you mean that Tony has found that reactive astrocytes are better at taking up amyloid than are regular astrocytes?

Gabrielle Strobel
Ben, do you think reactive gliosis could slow the normal stream of lactate from glia to neurons and thus starve them? I believe it's known that degenerating neurons run low on adenosine-5'-triphosphate (ATP) before they die, and there are many studies on a "hypometabolic" state of degenerating neurons.

Wenan Qiang
Glia activation is a cellular response to brain injury. In chronic glial activation, astrocytes will lose their neuronal support function. This is, therefore, detrimental to neurons.

Ben Barres
Wenan, Mike Sofroniew’s paper shows that reactive gliosis is important in keeping neurons alive after injury. If he blocks gliosis, the neurons die at a much higher rate. But it is not clear if that is related to their BBB function or to neurotrophic support of neurons, or other mechanisms.... Gabrielle, there has been a great deal of work on division of metabolic labor between astrocytes and neurons. All that work has been done with normal astrocytes. I am not aware of studies where people have addressed whether reactive astrocytes share metabolic pathways with normal astrocytes or not. It seems like that would be an important avenue of investigation, given the points you raise.

Linda Van Eldik
I think the key is to think of it as a delicate balance. Glia activation is probably generally beneficial, such as in acute brain injuries. But when it is chronic, as in AD, the detrimental responses may outweigh the beneficial responses, and then it has deleterious consequences to the brain.

Ben Barres
What happens to ApoE expression/secretion in reactive gliosis, Linda?

Linda Van Eldik
Ben, ApoE expression is upregulated by Aβ in activated astrocytes, at least in culture.

Gabrielle Strobel
Linda, is that "because" the astrocytes crank up their ability to clear Aβ via ApoE?

Linda Van Eldik
Gabrielle, I'm not sure of the mechanism, but we published a paper with Mary Jo LaDu showing that the Aβ stimulation of ApoE production requires the LDL receptor (LaDu et al., 2001).

Ben Barres
Linda, thanks for the information. I didn't know! Does ApoE bind to Aβ? I am just wondering if Aβ is a normal signaling molecule (at low levels) and whether ApoE helps deliver that signal to other cells?

Gabrielle Strobel
Ben, I believe it does. Dave Holtzman's hypothesis is that ApoE helps clear Aβ, and when it is not properly lipidated, or is in the ApoE4 isoform, it does a poor job of that and instead promotes deposition. Correct me if that's wrong, Linda.

Linda Van Eldik
ApoE definitely binds Aβ, with E3 binding better than E4.

Wenan Qiang
Does that mean Aβ metabolism requires ApoE?

Gabrielle Strobel
Wenan, I believe that is the implication. Last week, three papers in the Journal of Biological Chemistry reported that loss of ATP-binding cassette transporter, subfamily A (ABCA), which shuttles out cholesterol, reduces ApoE greatly but does not lower amyloid deposition in AD mouse models (see ARF related news story).

Linda Van Eldik
Aβ is a signaling molecule. It can bind to various cellular receptors and stimulate signal transduction pathways in the glia (at least in astrocytes and microglia) and in the neurons. It stimulates glia activation responses and it stimulates neuronal dysfunction/death.

Ben Barres
Linda, can you clarify? Are there known receptors for Aβ? (Sorry if that's ancient history.) What about the role of clusterin/ApoJ in all this? Does ApoJ also bind to Aβ? I ask because I am really impressed by how high the levels of ApoJ are in astrocytes in vivo (based on our unpublished gene chip data). Come to think of it, I do recall an old paper of Jerry Silver’s where he shows profound effects of Aβ on the phenotype of astrocytes (see, for example, Canning et al., 1993). I wonder what receptors mediate that.

Linda Van Eldik
ApoJ also binds Aβ. Tuck Finch and Grant Krafft/Bill Klein published papers showing that ApoJ can affect Aβ's ability to polymerize. Clusterin (ApoJ) alters the aggregation of amyloid-β peptide (Aβ1-42) and forms slowly sedimenting Aβ complexes that cause oxidative stress (see Oda et al., 1995). It promotes oligomeric forms of Aβ, and thereby enhances toxicity. Aβ can bind to a number of different receptors, including receptor for advanced glycation end products (RAGE), scavenger receptors, a receptor complex described by Gary Landreth (see Bamberger et al., 2003)....

Ben Barres
Has anyone looked at whether Aβ binding to ApoJ or ApoE enhances or hinders receptor interactions with lipoprotein receptor-related protein (LRP), etc.?

Gabrielle Strobel
Ben, Dave Holtzman also had a paper, I think in PNAS, about knocking down ApoJ in AβPP transgenics and looking at effect on amyloid. I don’t recall the phenotype, but can send you the citation (see DeMattos et al., 2002). Linda probably knows better than I.

Linda Van Eldik
Mary Jo LaDu also has some data relevant to that issue (see, for example, LaDu et al., 2000 reporting that ApoE mediates Aβ effects on astrocytes; Manelli et al., 2004 on effects of ApoE isoform on Aβ interactions; Tokuda et al., 2000 on the effect of lipidation on ApoE/Aβ interactions.

Ben Barres
Linda, so I guess the question is whether activation of any of those receptors would be sufficient to mediate known Aβ signaling effects like the induction of reactive gliosis; it seems unlikely to me. Has anyone taken tagged Aβ (perhaps in oligomeric form) and screened a cDNA library yet for receptors?

Gabrielle Strobel
I don't know.

Ben Barres
I saw a paper from Klein showing that Aβ oligomers bound to synapses, but I don't think he looked at whether there was binding to glia, as well (see Lacor et al., 2004).

Gabrielle Strobel
Yes, I seem to recall he saw punctate binding on cultured neurons and then tried to isolate what he thinks is a receptor complex.

Ben Barres
Gabrielle, that sounds pretty interesting! I don't see how the field can move forward in understanding Aβ actions without elucidating the receptors that mediate its effects. I am particularly interested in whether Aβ serves a normal signaling role, for instance, in the normal developing or normal adult brain. But I don't know if there is any work yet that pertains to this.

Linda Van Eldik
Take a look at our paper in 2000 (see LaDu et al., 2000). We found if we blocked ApoE receptors, then the ability of Aβ to stimulate IL-1b and ApoE production in glia were blocked. The mechanism is so far unknown.

Ben Barres
Linda, that's very interesting—I didn't know! Which ApoE receptors are expressed by astrocytes? Is it known?

Linda Van Eldik
We haven't looked for glia receptors, but oligomeric Aβ definitely can stimulate glia activation. We did a study with Mary Jo LaDu showing differential effects of oligomeric versus fibrillar Aβ on glia-induced inflammatory responses. Oligomeric Aβ is an excellent activator of glia (see White et al., 2005).

Ben Barres
We have a good rat brain cDNA library, Linda, if you would like to screen it for glial receptors!

Linda Van Eldik
Astrocytes express at least low-density lipoprotein receptor (LDLR) and LRP, but I'm not sure about any others.

Ben Barres
Linda, I will check our data and let you know.

June Kinoshita
I'm curious about aging-related changes in glia themselves. How does aging affect the normal function of glia, in particular, their role in maintaining healthy neuronal functions, and also, how does aging alter the reactive response of glia?

Ben Barres
June, I know that reactive gliosis is not a robust property of neonatal or early postnatal brain. I believe that developing astrocytes only gain the ability to become reactive when they finish dividing and maturing about P14 (in rodents, I mean). Quite possibly, this is because immature astrocytes are very similar (or the same) as reactive astrocytes, but that is a total guess.

Wenan Qiang
June, cellular redox balance setup is changing along with aging.

Ben Barres
June, but I think those are great questions. Never thought about them before and am not aware of relevant work. I also think that it would be very interesting to know the extent to which aging affects the number of normal glia. No one’s looked at that, to my knowledge.

Gabrielle Strobel
Are there studies comparing the transcriptional profile of normal versus activated astrocytes, or young versus old? Given that astrocytes influence neurons in many different ways—metabolic, neurotrophic signals, cholesterol/ApoE, etc. —it might be interesting to know what changes as they become increasingly activated, or simply as they age.

Ben Barres
We have just been doing some gene chip work, Gabrielle, transcriptional profiling of astrocytes at various stages of development. We now have the ability to compare reactive astrocytes with the normal astrocytes, and those experiments are on the drawing board. There is a postdoc joining the lab soon who hopes to work on this.

Gabrielle Strobel
Ben, to follow up on an earlier point: The only two physiological roles for Aβ (not AβPP) that I am aware of are modulating synaptic activity and regulating the levels of cholesterol and sphingomyelin. I am not aware of a physiological signal transduction role that has good data.

Ben Barres
However, I am sure that in terms of aging it will be extremely difficult to isolate astrocytes from aging brain. But I've been seeing some very nice work with laser capture from specific cell types in human brain, so it might be possible to do this for aging astrocytes in sections of human brain. For instance, see the beautiful work of Arnon Rosenthal looking at gene expression by human dopaminergic neurons (see, for example, Grimm et al., 2004).

Gabrielle Strobel
Ben, that sounds like a very interesting project. Is it possible to include some astrocytes from disease states?

Ben Barres
Gabrielle, my understanding of the work by Malinow is that he did not address whether Aβ has a normal physiological role in a normal brain, but only in tissue in which it had been overexpressed. It would be fantastic if he would look at whether it has a similar role in normal brain (as you say).

Gabrielle Strobel
Ben, I agree. The work on Aβ regulating cholesterol sphingomyelin synthesis, however, is done with physiological levels of Aβ. It's by Tobias Hartmann and just came out in Nature Cell biology last week (see ARF related news story).

Linda Van Eldik
Joe Rogers’ lab has developed a nice method for culturing glia from AD brain samples with short postmortem intervals.

Ben Barres
Linda, I am very skeptical about studies of astrocytes cultured from brain these days because we are finding that most astrocytes instantly die in culture and that the few that survive are either glial progenitors (which persist in adult brain) or newly generated immature glia from glial progenitors. To be sure, there are many similarities among all the astrocyte stages, but this is a caveat.

Linda Van Eldik
Ben, all cultured cells have some caveats associated with them. They are good for doing certain studies, like defining mechanisms, signaling, etc. However, we also have data from the mouse where infusion of oligomeric Aβ induces a robust glia activation and induction of proinflammatory cytokines like IL-1b, TNFα, and S100B (see Kim et al., 2004).

Ben Barres
Linda, that's very interesting. I had somehow missed the paper. In our studies of normal astrocytes we do not see any expression of TNFα or most of the usual cytokines, even in development, which may suggest that reactive astrocytes are quite different from immature astrocytes.

Linda Van Eldik
Ben, actually, I think the IL-1 and TNF are being produced by the microglia, and the S100B by the astrocytes. We haven't done colocalization studies in the mouse brain tissue, but did in glial cultures.

Ben Barres
Linda, that makes sense! Thanks for the reference! Though I am concerned that the cell types that survive from aging brain may actually be a different cell type—antigenic identification is important. I am always puzzled about the relationship between microglial activation and reactive astrocytosis—which comes first?

Linda Van Eldik
Ben, it depends on which endpoints you are measuring. The TNFα is one of the earliest cytokines to go up, IL-1 next, then iNOS and S100B in astrocytes. But there is a spectrum of responses occurring at different times after the stimulus. So it's not easy to say one comes first.

June Kinoshita
Ben, you point out in the background text that astrocytes and oligodendrocytes express more AβPP than do neurons. Has anyone looked at the effects of familial AD (FAD) mutations or of AβPP overexpression in astrocytes and oligodendrocytes?

Ben Barres
June, a very interesting question. I think so far the focus has been on the neurons, although I know there has been previous work showing that astrocytes secrete enormous amounts of certain AβPP splice forms like sAβPP. What these splice forms might do seems understudied, as well. I think I've seen some stuff about possible trophic effects. One problem is that some of these proteins are heavily glycosylated, which may be important to their function, but in most studies recombinant forms that are not properly modified are studied.

Gabrielle Strobel
Ben, yes, sAβPPα is usually regarded as a neurotrophic form, the "good" product of α-secretase cleavage, and many studies in the field are now focusing on ways to shift AβPP cleavage away from a BACE-γ pathway and toward this α pathway.

Chiara Cupidi
What about the role of glia in white matter? In corticobasal degeneration, in multiple system atrophy (MSA), and in AD, too, pathological proteins are often deposited there. Can these proteins create axonal dysfunction or lead to neuronal damage by retrograde or anterograde transport?

Gabrielle Strobel
Chiara, a great question. John Trojanowski and Virginia Lee just had a J. Neurosci paper (see Higuchi et al., 2005) about this, saying that tau filaments form in oligodendrocytes in animal models of cerebellar and brainstem atrophy (CBA) and frontotemporal dementia with parkinsonism (FTDP). And they also proposed that the toxic effect on neurodegeneration goes via axonal transport. We are also planning a live discussion with Phil Landfield, which will focus on oligodendroglia in neurodegeneration.

June Kinoshita
Ben, going back to your comment about isolating astrocytes from aging brain, can you comment about what the difficulties are? I've also often wondered whether anyone has attempted to count astrocytes in postmortem brain, comparing normal and AD tissues. Is this technically really formidable?

Ben Barres
June, counting astrocytes in brain, say, in AD and in normal aging, would require much better astrocyte markers than exist today. We have just identified, through our gene chip studies, some better markers and are working with a company to make antibodies available quickly to everybody.

June Kinoshita
That sounds great! Let us know when you've got them, and we'll add them to our antibody database.

Linda Van Eldik
Astrocytes can be isolated from aging brain, but they don't survive as well in culture and grow very slowly. Tuck Finch, Joe Rogers, Sue Griffin, and others have cultured astrocytes from aged rodents and from AD brain.

Gabrielle Strobel
Why are there so many leads but few solid data on glia that are then widely accepted? Are the big hurdles more due to lack of interest or technical challenges? Lack of reliable and specific glial markers appears to be one.

Ben Barres
Gabrielle, I guess there are so many hard technical challenges to studying glia, starting with the lack of good markers and the lack of good culture models for mature astrocytes (that will change soon, as we've made some interesting progress on that).

Gabrielle Strobel
What do you think is the function of the glial AβPP you see expressed so abundantly? Hui Zheng at Baylor has data on the role of AβPP in synapse formation (synapses are defective without it), but I am not aware if she distinguishes between neuronal or glial AβPP (see Yang et al., 2005).

Ben Barres
Gabrielle, yes, I saw the very interesting work of Zheng at Baylor. And Vivian Budnik just had a paper on the role of AβPP in synaptogenesis in flies (see Ashley et al., 2005 and ARF related news story). I hadn't thought of the point you raise about how they can distinguish between glia and neuronal forms, which certainly is a good question, given the recent work on the role of Schwann cells in synaptogenesis at the neuromuscular junction.

Gabrielle Strobel
Yes, we've reached the end of the hour. I certainly have a lot of other questions, but we'll follow up on the topic in future chats. Apologies for the software hiccups, and thank you all for coming.

Ben Barres
Before everyone goes, I just want to say this has been a great chat for me—I've learned a lot! Thank you, all!

Gabrielle Strobel
I have to go but want to stress that you can all stay and continue the conversation as long as you like. Good bye for now.

Linda Van Eldik
Well, I must go, too. Just want everyone to know that targeting neuroinflammation selectively has great potential for AD therapy in the future. Perhaps that will be the subject of a future chat. Bye!

Chiara Cupidi
 Bye!

Background

Background Text

By Ben Barres

What is the role of glia in neurodegenerative disease? Recent studies increasingly suggest that glia, both microglia and astrocytes, actively participate in inducing neuron death in diverse diseases from glaucoma and Alzheimer disease to amyotrophic lateral sclerosis. For instance, neuronal expression of the mutant SOD1 gene that causes familial ALS is insufficient to cause motor neuron loss in mice. Microglia infected by the HIV-1 virus appear to actively kill neurons, thereby inducing AIDS dementia. Reactive gliosis is prominent in all neurodegenerative diseases, and recent studies increasingly implicate the severe gliosis at the optic nerve head in the loss of retinal ganglion cells in glaucoma. In many ways, progress in understanding whether glia contribute to the pathophysiology of neurodegeneration has been limited by poor understanding of their normal roles. The purpose of this mini-review is to summarize briefly some of the recent progress in understanding the normal function of glial cells and to consider how these new advances may help us to better understand the role of glia in neurodegenerative disease. Although I will focus primarily on astrocytes, microglia and even oligodendrocytes are increasingly suggested to contribute to neurodegenerative disease pathophysiology, as well, but are beyond the scope of this commentary.

Perhaps the most interesting advance concerning astrocytes in recent years is the increasing realization that astrocytes actively contribute to the formation, function, plasticity, and elimination of synapses during development and in maturity (1). What implication might these new findings have for understanding neurodegenerative disease? For one thing, in Alzheimer disease (AD) much synapse loss occurs before neuron loss. The cause of synapse loss in AD is not known, but synapses that function poorly may be eliminated. Although the mechanism of normal synapse elimination is poorly understood, recent studies directly implicate glial cells as actively contributing to this process (1). Interestingly, the amyloid-ß peptide depresses synapse function (2) and could therefore conceivably trigger synapse elimination (3). Neurons are generally considered the main source of ß amyloid, but our unpublished gene profiling studies indicate that glial cells, both astrocytes and oligodendrocytes, express higher levels of APP and its homologues than do neurons. Glia also produce high levels of many APP processing enzymes, and thus could be a quantitatively important source of Aß, as well (J. Cahoy and B. Barres, unpublished observations). Important questions for future study are the roles of reactive glial cells in normal synapse formation and function, and whether reactive glia might up-regulate production of toxic forms of ß amyloid.

Another area of recent progress has been in understanding the division of metabolic labor between neurons and glia. Although the point of dividing metabolic labor is still unclear, an important confirmation of the functional existence of this division has recently been published (4). Rather than glucose being consumed and then oxidized directly by neurons, neuronal activity drives astrocytes to produce lactate, which is then transferred to the neurons for energy production. An as-yet unexplored question is whether this normal metabolic division of labor might be perturbed by reactive gliosis and whether this might have detrimental consequences for the health of neurons. For instance, this new metabolic study revealed dramatic changes in nicotinamide adenine dinucleotide (NAD) levels in both the neurons and the glia during neuronal activity (4), and maintaining normal NAD levels is of crucial importance in preventing axonal degeneration (5). A related area of investigation is the nature of the glial signals that control neuron survival. Unlike peripheral neurons whose survival can be maintained in culture by known neurotrophic signals, most CNS neurons quickly undergo apoptosis in a culture dish and the signals that normally promote their survival are unknown. Astrocytes have been suggested to secrete signals that induce neuronal survival in vivo. Although this remains to be proven, astrocytes in culture clearly secrete a signal that is crucial for neuronal survival, but the identity of this signal and whether it contributes to normal CNS neuron survival in vivo are not known. This raises additional important questions relevant to understanding why CNS neurons die in neurodegenerative disease. Do normal and reactive astrocytes in vivo continue to make this neurotrophic signal, and might diminishing neuronal activity somehow decrease production or secretion of neurotrophic factors by astrocytes?

Astrocytes not only ensheath synapses in the normal brain, but they widely ensheath capillaries and arterioles. What is their normal role at blood vessels and does it become perturbed in neurodegenerative disease? Astrocytes secrete signals that help induce vascular growth and remodeling. Recent studies have found that astrocytes also release signals that control vascular contractility and blood flow, and that neuronal activity controls this gliovascular signaling (6-8). Some studies have also suggested a role for astrocytes in inducing and maintaining the blood-brain barrier, but, as is true for many other hypothetical roles of astrocytes, the evidence remains weak and the signals responsible are not known. Clearly, any disturbance of the neuro-gliovascular unit may have serious consequences for neuron health and function. The extent to which this, or blood-brain barrier disturbance, contributes to AD and other neurodegenerative diseases are important questions for future study.

In thinking about the potential role of astrocytes in neurodegenerative disease, it is interesting to reflect that there are not yet good markers of astrocytes that enable their clear visualization and quantification in human brain sections. GFAP antibodies have been widely used for this purpose, but are inadequate because they predominantly bind to white matter (fibrous) but not gray matter (protoplasmic) astrocytes. The old idea that astrocytes survive most brain insults whereas neurons are preferentially lost is no longer tenable. Mature brain astrocytes undergo apoptosis just as quickly as do neurons when placed into tissue culture (9), and astrocyte apoptosis in vivo is increasingly observed after various CNS insults such as ischemia. A dramatic decrease in astrocyte number has been reported in major depression (10). Given these considerations and the lack of almost any good data on the normal number of astrocytes in AD and other neurodegenerative diseases, who is to say that degeneration of astrocytes does not precede loss of neurons in AD?

An interesting question is whether reactive gliosis, present in normal aging brain, accounts for the susceptibility of the aging brain to AD. Perhaps the strongest argument that astrocytes participate directly in the pathophysiology of AD is the finding that the ApoE4 allele enhances the chance of having AD. The vast majority of ApoE is produced and secreted by astrocytes; however, here, again, there is little good evidence about why astrocytes secrete lipoprotein particles. In culture, and likely in vivo, astrocytes secrete two classes of lipoprotein particles, one class containing ApoE and the other class containing ApoJ (11). The role of these particles is unknown. They presumably supply neurons and oligodendrocytes with lipid precursors such as triglycerides and esterified cholesterol. But they may also carry as-yet unidentified hydrophobic signals, and ApoE itself may be an important signaling molecule. Interestingly, reactive glial cells secrete more ApoE than normal and are also reported to secrete more ß amyloid (12). Reactive glial cells may also secrete cytokines that alter microglial function. The role of reactive glia, and whether they are harmful or helpful in neurodegenerative disease, remains a provocative and important question for future research.

References:
1. Allen NJ, Barres BA (2005) Signaling between glia and neurons: focus on synaptic plasticity. Curr. Opin. Neurobiol., in press

 

2. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. (2003) APP processing and synaptic function. Neuron 37, 925-37. Abstract

 

3. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Nat Neurosci. 2005 Aug ; 8(8):1051-8. Abstract

 

4. Kasischke KA, Vishwasrao HD, Fisher PJ, Zipfel WR, Webb WW. (2004) Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305, 99-103. Abstract

 

5. Araki T, Sasaki Y, Milbrandt J. (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. 305,1010-3. Abstract

 

6. Mulligan SJ, MacVicar BA. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. (2004) Nature 431, 195-9. Abstract

 

7. Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M. Signaling at the gliovascular interface. (2003) J Neurosci. 23, 9254-62. Abstract

 

8. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G. (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 6, 43-50. Abstract

 

9. Cahoy JD, Christopherson KS, and Barres BA (2005) Purification and characterization of mature astrocytes from the postnatal rodent CNS. Soc. Neurosci. Abstr, No. 387.2.

 

10. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA. (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 45, 1085-98. Abstract

 

11. DeMattos RB, Brendza RP, Heuser JE, Kierson M, Cirrito JR, Fryer J, Sullivan PM, Fagan AM, Han X, Holtzman DM. Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice. (2001) Neurochem Int. 39, 4 15-25. Abstract

 

12. Bates KA, Fonte J, Robertson TA, Martins RN, Harvey AR. (2002) Chronic gliosis triggers Alzheimer's disease-like processing of amyloid precursor protein. Neuroscience 113, 785-96. Abstract

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  1. Designer Drugs to Target Inflammation in AD
    With this comment I'll add a component focused on microglia to this discussion. Accumulating evidence supports the role of microglia in neurodegenerative diseases. In AD, microglia activation has been associated with either beneficial or toxic effects in AD pathogenesis. Stimulation of microglial activation by various methods (entorhinal cortex lesion, passive and active Aß vaccine, LPS injection), consistently leads to reduced amyloid deposition, suggesting that microglial activation plays a major role in plaque clearance. On the other hand, compelling in vitro and in vivo data indicate that chronic inflammatory alterations surrounding neuritic plaques, including microglia and astroglial activation, contribute to neuronal injury (Rogers et al., 1996; Akiyama et al., 2000). It is conceivable that different signaling pathways were activated by specific stimuli, including Aß oligomers/fibrils and neuronal-derived factors, at different disease stages and/or in different microenvironments. Depending on which sets of downstream genes get expressed, activated microglia could either fulfill their role in Aß clearance, or be engaged in promoting neuronal injury, or both. Indeed, passive Aß immunotherapy was found to attenuate the pathology and improve cognition in AD animal models (Janus et al., 2000; Morgan et al., 2000), indicating that it is possible to promote the beneficial effects of microglia activation selectively. However, active Aß immunization in humans was linked to 6 percent of patients developing meningoencephalitis in the clinical trial (Senior, 2002; Orgogozo et al., 2003), suggesting that promoting microglia activation could also be associated with serious side effects. Furthermore, LPS stimulation of microglia recently was reported to accelerate tau pathology in a mouse model of AD (Kitazawa et al., 2005).

    Another potential therapeutic approach is to identify and block specific pathogenic pathways selectively while preserving the beneficial functions of those cells. Here, one important underlying question is whether the potential toxic effects of microglia activation are an early event that is significant for disease progression or a late phenomenon that simply correlates with the pathology. Earlier neuropathological analysis implicated microglia as a late-stage response based on the selective clustering of activated microglia around the dense-core plaques. However, recent studies suggest that inflammatory mechanisms are more likely involved in the early steps of the pathological cascade. In-vivo imaging of microglia with two-photon laser-scanning microscopy revealed the amazingly mobile fine branches of "resting" microglia, which provide extensive surveillance and show a rapid chemotactic response to tissue injury (Davalos et al., 2005; Nimmerjahn et al., 2005 (see Web movies). These findings are highly consistent with microglia being the first line of defense for the neural parenchyma and playing an active role from early on.

    Numerous epidemiological studies found that long-term, but not short-term, use of NSAIDs was associated with a lower risk of AD, suggesting a preventive role (in't Veld et al., 1998; Zandi and Breitner, 2001). In clinical trials, however, some NSAIDs did not slow cognitive decline in patients who already had mild to moderate AD (Aisen et al., 2003; Senior, 2003). These results, too, are consistent with the notion that the toxic effects of microglia activation are an early event and thus may require an even earlier intervention (Zandi and Breitner, 2001; Wyss-Coray and Mucke, 2002; van Gool et al., 2003). Nonfibrillar Aß, which may be the major pathogenic form of Aß in the early stages of AD, was found to stimulate microglia to induce neurodegeneration in cell culture studies. Dimeric and trimeric assemblies of Aß42 isolated from amyloid deposits elicited profound microglia-mediated neurotoxicity in hippocampal neurons (Roher et al., 1996). Further studies indicate that microglial stimulation with soluble Aß resulted in secretion of toxic factors, including cathepsin B, iNOS, and superoxide, that mediated neurodegeneration or inhibition of long-term potentiation (Gan et al., 2004; Wang et al., 2004).

    To identify signaling pathways underlying the toxic effects of microglia activation, we recently found that NF-?B signaling, a transcription factor that mediates immune and inflammatory responses and controls the expression of both iNOS and cathepsin B, is critical in microglia-mediated Aß? toxicity (Chen et al., 2005). Targeted inhibition of NF-?B signaling in microglia strongly attenuated the toxicity of soluble Aß in mixed cortical cultures, suggesting that microglial NF-?B signaling may play a critical role in mediating the toxic effects of AD-related inflammatory responses. Inhibiting NF-?B signaling by activation of SIRT1 deacetylase is also neuroprotective. Our findings indicate that inhibiting the activation of NF-?B or of NF-?B-dependent microglial gene products such as cathepsin B could block this pathogenic cascade and increase neuronal survival in AD. Interestingly, proinflammatory cytokine-stimulated NF-?B activation was recently found to decrease phagocytosis of Aß fibrils, indicating additional pathological effects of microglial NF-?B signaling. NF-?B activation, however, did not affect phagocytosis stimulated by anti-Aß antibody (Koenigsknecht-Talboo and Landreth, 2005). These studies suggest that inactivating NF-?B signaling may enable selective attenuation of the toxic effects of microglia activation without affecting beneficial functions, such as Aß clearance. It remains to be determined, however, whether this is the case in vivo. Nevertheless, identification of critical signaling pathways underlying microglia-mediated neurotoxicity would facilitate the discovery of selective drug targets that are more directly responsible for neurodegeneration in AD.

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References

Webinar Citations

  1. Are Glia Active Participants in Neurodegenerative Disease?

News Citations

  1. Got Plaques? Astrocytes to the Rescue!
  2. ABCA1 Loss Lowers ApoE, Not Amyloid; New ApoE Immunology
  3. A Better GRIP on the Aβ-Lipid Connection
  4. APP Has a Role in Synaptic Development

Paper Citations

  1. . APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.
  2. . Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.
  3. . Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science. 2004 Jul 2;305(5680):99-103. PubMed.
  4. . Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004 Aug 13;305(5686):1010-3. PubMed.
  5. . Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature. 2004 Sep 9;431(7005):195-9. PubMed.
  6. . Signaling at the gliovascular interface. J Neurosci. 2003 Oct 8;23(27):9254-62. PubMed.
  7. . Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 2003 Jan;6(1):43-50. PubMed.
  8. . Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999 May 1;45(9):1085-98. PubMed.
  9. . Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice. Neurochem Int. 2001 Nov-Dec;39(5-6):415-25. PubMed.
  10. . Chronic gliosis triggers Alzheimer's disease-like processing of amyloid precursor protein. Neuroscience. 2002;113(4):785-96. PubMed.
  11. . Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron. 1999 Jun;23(2):297-308. PubMed.
  12. . Apolipoprotein E and apolipoprotein E receptors modulate A beta-induced glial neuroinflammatory responses. Neurochem Int. 2001 Nov-Dec;39(5-6):427-34. PubMed.
  13. . beta-Amyloid of Alzheimer's disease induces reactive gliosis that inhibits axonal outgrowth. Exp Neurol. 1993 Dec;124(2):289-98. PubMed.
  14. . Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress. Exp Neurol. 1995 Nov;136(1):22-31. PubMed.
  15. . A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci. 2003 Apr 1;23(7):2665-74. PubMed.
  16. . Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10843-8. PubMed.
  17. . Apolipoprotein E receptors mediate the effects of beta-amyloid on astrocyte cultures. J Biol Chem. 2000 Oct 27;275(43):33974-80. PubMed.
  18. . ApoE and Abeta1-42 interactions: effects of isoform and conformation on structure and function. J Mol Neurosci. 2004;23(3):235-46. PubMed.
  19. . Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid beta peptides. Biochem J. 2000 Jun 1;348 Pt 2:359-65. PubMed.
  20. . Synaptic targeting by Alzheimer's-related amyloid beta oligomers. J Neurosci. 2004 Nov 10;24(45):10191-200. PubMed.
  21. . Differential effects of oligomeric and fibrillar amyloid-beta 1-42 on astrocyte-mediated inflammation. Neurobiol Dis. 2005 Apr;18(3):459-65. PubMed.
  22. . Molecular basis for catecholaminergic neuron diversity. Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13891-6. PubMed.
  23. . Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production. Neurobiol Aging. 2004 Apr;25(4):431-9. PubMed.
  24. . Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies. J Neurosci. 2005 Oct 12;25(41):9434-43. PubMed.
  25. . Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci Lett. 2005 Aug 12-19;384(1-2):66-71. PubMed.
  26. . Fasciclin II signals new synapse formation through amyloid precursor protein and the scaffolding protein dX11/Mint. J Neurosci. 2005 Jun 22;25(25):5943-55. PubMed.

Other Citations

  1. Gabrielle@alzforum.org

Further Reading

Papers

  1. . Risk of Alzheimer's disease and duration of NSAID use. Neurology. 1997 Mar;48(3):626-32. PubMed.