Ben Barres		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.

View Transcript of Live Discussion — Posted 5 December 2005

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

	Comments on Live Discussion
	Comment by:  Li Gan
	Submitted 18 October 2005  |  Permalink	Posted 18 October 2005
	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...  Read more 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. References: Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ; Alzheimer's Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2819-26. Abstract Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L. SIRT1 protects against microglia-dependent beta amyloid toxicity through inhibiting NF-kappa B signaling. J Biol Chem. 2005 Sep 23 Abstract Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005 Jun;8(6):752-8. Epub 2005 May 15. Abstract Gan L, Ye S, Chu A, Anton K, Yi S, Vincent VA, von Schack D, Chin D, Murray J, Lohr S, Patthy L, Gonzalez-Zulueta M, Nikolich K, Urfer R. Identification of cathepsin B as a mediator of neuronal death induced by Abeta-activated microglial cells using a functional genomics approach. J Biol Chem. 2004 Feb 13;279(7):5565-72. Epub 2003 Nov 10. Erratum in: J Biol Chem. 2004 May 28;279(22):23845. Abstract in 't Veld BA, Launer LJ, Hoes AW, Ott A, Hofman A, Breteler MM, Stricker BH. NSAIDs and incident Alzheimer's disease. The Rotterdam Study. Neurobiol Aging. 1998 Nov-Dec;19(6):607-11. Abstract Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):979-82. Abstract Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci. 2005 Sep 7;25(36):8240-9. Abstract Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):982-5. Erratum in: Nature 2001 Aug 9;412(6847):660. Abstract Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005 May 27;308(5726):1314-8. Epub 2005 Apr 14. Abstract Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci. 2005 Sep 28;25(39):8843-53. Abstract Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003 Jul 8;61(1):46-54. Abstract Rogers J, Webster S, Lue LF, Brachova L, Civin WH, Emmerling M, Shivers B, Walker D, McGeer P. Inflammation and Alzheimer's disease pathogenesis. Neurobiol Aging. 1996 Sep-Oct;17(5):681-6. Review. Abstract Roher AE, Chaney MO, Kuo YM, Webster SD, Stine WB, Haverkamp LJ, Woods AS, Cotter RJ, Tuohy JM, Krafft GA, Bonnell BS, Emmerling MR. Morphology and toxicity of Abeta-(1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer's disease. J Biol Chem. 1996 Aug 23;271(34):20631-5. Abstract Senior K. Dosing in phase II trial of Alzheimer's vaccine suspended. Lancet Neurol. 2002 May;1(1):3. No abstract available. Abstract van Gool WA, Aisen PS, Eikelenboom P. Anti-inflammatory therapy in Alzheimer's disease: is hope still alive? J Neurol. 2003 Jul;250(7):788-92. Review. Abstract Wang Q, Rowan MJ, Anwyl R. Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J Neurosci. 2004 Jul 7;24(27):6049-56. Abstract Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002 Aug 1;35(3):419-32. Review. Abstract Zandi PP, Breitner JC. Do NSAIDs prevent Alzheimer's disease? And, if so, why? The epidemiological evidence. Neurobiol Aging. 2001 Nov-Dec;22(6):811-7. Review. No abstract available. Abstract View all comments by Li Gan

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