The paper by Ziv et al. brings together two often disparate fields of study: immunology and neuroscience. The group of Michal Schwartz is one of a relatively few in the world who draws on tools of both trades to study how the immune and nervous systems intersect to influence brain function.

The authors propose the interesting hypothesis that the hippocampal (and olfactory) neurogenesis required for optimal functioning of the adult brain is dependent on cues from peripheral immune cells. It had been shown previously that inflammatory activation of the peripheral immune system can diminish neurogenesis in the brain. This work suggests that the converse, that is, that neurogenesis depends in some way on immune support, may also hold true.

The authors' use of SCID and nude mice for these studies is quite innovative, and the experiments carefully control for differences in genetic background that are known to influence adult neurogenesis. The decrement in BrdU+ cells, and specifically BrdU/DCX and BrdU/NeuN cells, in the immune-deficient mice is consistent with their...  Read more

The paper by Ziv et al. brings together two often disparate fields of study: immunology and neuroscience. The group of Michal Schwartz is one of a relatively few in the world who draws on tools of both trades to study how the immune and nervous systems intersect to influence brain function.

The authors propose the interesting hypothesis that the hippocampal (and olfactory) neurogenesis required for optimal functioning of the adult brain is dependent on cues from peripheral immune cells. It had been shown previously that inflammatory activation of the peripheral immune system can diminish neurogenesis in the brain. This work suggests that the converse, that is, that neurogenesis depends in some way on immune support, may also hold true.

The authors' use of SCID and nude mice for these studies is quite innovative, and the experiments carefully control for differences in genetic background that are known to influence adult neurogenesis. The decrement in BrdU+ cells, and specifically BrdU/DCX and BrdU/NeuN cells, in the immune-deficient mice is consistent with their hypothesis.

However, it is the reconstitution experiments examining neurogenesis after replenishing the immune system with normal or T cell-depleted splenocytes that to me forms the crux of this study. Restoration of normal neurogenesis by the introduction of donor splenocytes is the definitive proof that the neuronal precursor cell population is intact and simply requires external activation from the added immune cells. The description of these experiments might have benefited from more detailed display of this data on which to evaluate the results. For instance, in Figure 2 showing the first of the reconstitution experiments, the number of BrdU/DCX+ cells per dentate gyrus after addition of normal splenocytes (panel d) appears comparable to the number of BrdU/DCX+ cells found in unreconstituted SCID mice at the same age (panel a). The intended comparison is to SCID mice reconstituted with T cell-depleted splenocytes, but data for the level of neurogenesis in untreated mice would have been a good control to include in the same panel.

The reconstitution experiments are especially important in evaluating the data shown in Figure 4, which presents data of the study of neurogenesis in nude mice. The very disrupted DCX staining in the nude mice of Figure 4c suggests that the gene defect in these mice may affect neurogenesis in ways independent of T cell function. After all, the mice are also nude, and have hair follicle deficits that may have nothing to do with alterations in the immune system. For these experiments, the authors do plot the data one would have liked to see for the SCID experiments; specifically, they show untreated nude vs. nude + splenocytes, demonstrating that there is significant recovery of newly dividing cells in the hippocampus. Here it is worth noting that PCNA staining does not equal neurogenesis (PCNA, like BrdU, does not distinguish between cell types), and the experiment could be stronger if it provided the same comparison (untreated nude vs. nude + splenocytes) for BrdU/DCX+ double labeled cells to show a specific effect on neuronal production.

One goal to tackle for follow-up work is to convincingly connect the function of peripheral T cells to the effector microglia in the brain, and to explain how microglia then act on progenitor cells to increase neurogenesis. The present work shows T cells in the ventricles, where they might be able to directly influence the turnover and/or differentiation of precursor cells in the subventricular zone (the source of neurogenesis for olfactory bulb interneurons). It would be fascinating to know how they signal to microglia in the parenchyma of the brain to activate precursor cells deep in the dentate gyrus. Identifying the signaling factors used to communicate between these distant areas will solve the spatial paradox that exists based on the data available so far.

This paper should serve to start the neuroscience community thinking more seriously about the interaction of body and mind. There may be a lot more to it than most researchers or clinicians now realize.

View all comments by Joanna Jankowsky

Excellent article, and studies done were well-controlled. This article provides further validation of the communication between the central nervous system and the immune system. In this article, the authors showed that T cells (of the immune system) that reside in the central nervous system (CNS) can influence both neurogenesis and cognitive functioning independently. Under normal conditions, the resident T cells and microglia in the CNS are barely detectable, but when neurogenesis was enhanced by housing rats in an enriched environment, both T cells and microglia were activated. When neurogenesis was examined in mutant mice deficient in T cells, the authors found that neurogenesis was decreased compared to the control mice. It is interesting that even when the mutant mice were housed in the enriched environment, this did not help in increasing neurogenesis, as is usually seen in normal animals. However, when the mutant mice were injected with "splenocytes" containing replenished T cells, increased neurogenesis was seen when compared to mice depleted for T cells. Furthermore, the...  Read more

Excellent article, and studies done were well-controlled. This article provides further validation of the communication between the central nervous system and the immune system. In this article, the authors showed that T cells (of the immune system) that reside in the central nervous system (CNS) can influence both neurogenesis and cognitive functioning independently. Under normal conditions, the resident T cells and microglia in the CNS are barely detectable, but when neurogenesis was enhanced by housing rats in an enriched environment, both T cells and microglia were activated. When neurogenesis was examined in mutant mice deficient in T cells, the authors found that neurogenesis was decreased compared to the control mice. It is interesting that even when the mutant mice were housed in the enriched environment, this did not help in increasing neurogenesis, as is usually seen in normal animals. However, when the mutant mice were injected with "splenocytes" containing replenished T cells, increased neurogenesis was seen when compared to mice depleted for T cells. Furthermore, the authors found that the influence of CNS T cells in neurogenesis is partly mediated by microglial cells, because when they gave the mice minocycline (a drug that inhibits microglial activity), a significant decrease in neurogenesis was seen compared to controls.

What is also interesting in this study is that mere activation of resident T cells in the CNS does not result in increased neurogenesis. The authors showed that the antigen (or protein) that induces T cell activation has to be specific (i.e., proteins involved in brain plasticity) for effective involvement in neurogenesis. This is demonstrated when they examined two different types of transgenic mice (one that expresses T cell receptors that recognize myelin basic protein—protein that is involved in axonal growth—and another that expresses T cell receptors that recognize ovalbumin—general protein); they found increased neurogenesis and enhance learning ability only in the transgenic mice that express T cell receptors that recognize myelin basic protein when compared to their control counterparts. The thoroughness of the experiments presented in this article provides good evidence that the immune system is involved in maintaining CNS integrity. As the authors suggest, the results of their experiment may partially explain the association between age-related decline in neurogenesis and decreased immune functioning related to aging.

Further corroboration is needed before the evidence can be convincingly accepted. With regard to its applicability in Alzheimer disease, the results of this study may be limited. It should, however, trigger thoughts on the role of the aging immune system in influencing brain function, as well as on the bidirectional communication between the CNS and the immune system.

View all comments by Teresita Briones

In the recent papers from the groups of Przedborski and Eggan, provocative evidence is reported that spinal motor neurons may die in SOD1 mutant mice because of soluble toxic factors released by SOD1 mutant astrocytes. This result is surprising because previous studies with chimeric SOD1 mutant mice have shown that expression of mutant SOD1 in microglia but not astrocytes is implicated in the neuron death. However, profound reactive astrocytosis occurs very early in mouse and human motor neuron diseases. This is true in the SOD1 mutant mice, where reactive astrocytosis is a dramatic feature of the disease, with prominent reactive astrocytosis occurring long before much motor neuron death occurs (Carlos Pardo, personal communication).

The new studies provide striking evidence that astrocyte-conditioned medium from SOD1 mutant astrocytes is toxic, as wild-type spinal motor neurons survive longer in culture when cultured alone or with wild-type astrocyte conditioned medium than with mutant astrocyte- conditioned medium. Thus, the lower survival of the spinal motor neurons...  Read more

In the recent papers from the groups of Przedborski and Eggan, provocative evidence is reported that spinal motor neurons may die in SOD1 mutant mice because of soluble toxic factors released by SOD1 mutant astrocytes. This result is surprising because previous studies with chimeric SOD1 mutant mice have shown that expression of mutant SOD1 in microglia but not astrocytes is implicated in the neuron death. However, profound reactive astrocytosis occurs very early in mouse and human motor neuron diseases. This is true in the SOD1 mutant mice, where reactive astrocytosis is a dramatic feature of the disease, with prominent reactive astrocytosis occurring long before much motor neuron death occurs (Carlos Pardo, personal communication).

The new studies provide striking evidence that astrocyte-conditioned medium from SOD1 mutant astrocytes is toxic, as wild-type spinal motor neurons survive longer in culture when cultured alone or with wild-type astrocyte conditioned medium than with mutant astrocyte- conditioned medium. Thus, the lower survival of the spinal motor neurons cannot be attributed to less production of neurotrophic factors by the mutant astrocytes. Together, these in-vitro and in-vivo findings directly implicate reactive astrocytes in the pathophysiology of spinal motor neuron death in the SOD1 mutant mice. One caveat is that in the in-vitro studies, the astrocytes that were studied were obtained from neonatal spinal cords long before any reactive gliosis actually occurs. However, neonatal astrocytes in culture have a similar phenotype to reactive astrocytes in vivo, and may in fact be comparable.

So how can these new observations of Przedborski and Eggan be reconciled with previous studies that found that chimeric SOD1 mutant mice with mutant SOD1 in microglia but not astrocytes is implicated in the neuron death? For one thing, it is unclear if mutant microglia were actually present in the astrocyte cultures used in these new studies. Steps were taken to minimize microglial contamination, but because astrocytes secrete high levels of microglial mitogens such as colony stimulating factor-1 (CSF1), microglia almost always heavily contaminate neonatal astrocyte cultures prepared by the commonly used methods of McCarthy and DeVellis. It would be good to repeat the study using more stringent methods of microglial elimination, such as immunopanning, and it would be important to confirm by immunostaining that microglia are in fact absent from the astrocyte-conditioned medium at the time it is harvested. It is also possible that mutant astrocytes release factors in culture that are toxic to motor neurons but that these factors are not actually secreted in vivo or are not toxic to the neurons in vivo. The only way to find out for sure, of course, will be to identify this toxic astrocyte factor. At the present time, it is difficult to think of a model that reconciles the previous in-vivo observations implicating mutant microglia with the present in-vitro observations implicating mutant astrocytes.

Assuming astrocytes make a toxic factor, what could be its nature? The possibility that it is glutamate has already been ruled out, as have been the obvious cytokine candidates. Moreover, the motor neurons undergo apoptosis. One possibility is that it is a factor that binds to, inhibits, or proteolyzes required trophic factors or culture substrates present in the culture medium that are required for long-term motor neuron survival.

Another possibility is that the toxic astrocytes alter the pH of the culture medium or lower antioxidant levels, which are both crucial parameters for good neuronal survival. Alternatively, a toxic factor could be released, such as a cytokine of some sort or an excitotoxin. Glutamate agonists have not been ruled out. For instance, homocysteine is an NMDA agonist that is exclusively made by astrocytes; other possibilities are aspartate and N-acetyl-aspartylglutamate, which all act on NMDA receptors. In addition, astrocytes have previously been shown to secrete high levels of NMDA potentiators such as L-glycine or D-serine, and it is possible that the mutant astrocytes secrete higher levels of these. Glutamate excitotoxicity can lead to apoptosis, so it would be important in future experiments to test whether the toxic astrocyte factor can be blocked by APV or other NMDA receptor blockers, as so far only kainate and AMPA receptor blockers have been tested.

A very interesting new paper by Don Cleveland’s group provides evidence, using laser capture studies of mRNA expression, that spinal motor neurons in the SOD mutant mice have elevated levels of several complement proteins. This raises the possibility that there is complement-induced toxicity. However, microglia and serum, which are both rich sources of the complete set of complement proteins required for the complement cascade to function, were not present in the motor neuron cultures; therefore, this seems an unlikely possibility. Moreover, complement-mediated toxicity would be expected to cause lysis and not necessarily apoptosis (though mild toxic insults are well documented to lead to apoptosis in neurons). Interestingly, the new Cleveland work also provides evidence for a strong upregulation of the serine biosynthetic pathway. Astrocytes have previously been shown to preferentially use the serine synthetic pathway, whereas neurons do not (a result we have recently confirmed by gene profiling of purified neural cell populations; Cahoy and Barres, unpublished observations). It is possible that SOD1 mutant neurons upregulate these pathways as they die, but a more likely possibility is that there was some contamination by reactive glial genes in these studies, a possibility that is suggested by the presence of other upregulated well-described astrocyte genes such as CD44 and aquaporin 4. This latter possibility again raises the possibility that the toxic factor being released by mutant astrocytes is D-serine or L-glycine.

Whatever the case, these new papers call attention to the important but still poorly understood roles of neuron-glial interactions in the pathophysiology of neurodegenerative disease.

View all comments by Ben Barres

These two papers by Nagai et al. (2007) and Di Giorgio et al. (2007) independently provide strong evidence that glial cells, and perhaps specifically astrocytes, bearing SOD1 mutations are responsible for degeneration and death of motor neurons in embryonic stem cell (ESC)-based co-cultures of primary neurons and glial cells. Motor neurons bearing SOD1 mutation did not degenerate in the absence of mutant glial cells.

While these elegant findings provide important insights into the interdependency between neurons and glial cells, and provide key data concerning the pathogenesis of human ALS associated with SOD1 mutation, their relevance to sporadic and other non-SOD1 related forms of human ALS is uncertain. Increasingly, it is becoming recognized that SOD1- associated ALS, and non-SOD1 forms of ALS may be driven through different pathogenetic cascade mechanisms. In SOD1 ALS, the accumulated protein within the conglomerated ubiquitinated inclusion bodies is mutated SOD1. In other, non-SOD1 forms of familial ALS, and sporadic ALS, the filamentous or skein-like ubiquitinated...  Read more

These two papers by Nagai et al. (2007) and Di Giorgio et al. (2007) independently provide strong evidence that glial cells, and perhaps specifically astrocytes, bearing SOD1 mutations are responsible for degeneration and death of motor neurons in embryonic stem cell (ESC)-based co-cultures of primary neurons and glial cells. Motor neurons bearing SOD1 mutation did not degenerate in the absence of mutant glial cells.

While these elegant findings provide important insights into the interdependency between neurons and glial cells, and provide key data concerning the pathogenesis of human ALS associated with SOD1 mutation, their relevance to sporadic and other non-SOD1 related forms of human ALS is uncertain. Increasingly, it is becoming recognized that SOD1- associated ALS, and non-SOD1 forms of ALS may be driven through different pathogenetic cascade mechanisms. In SOD1 ALS, the accumulated protein within the conglomerated ubiquitinated inclusion bodies is mutated SOD1. In other, non-SOD1 forms of familial ALS, and sporadic ALS, the filamentous or skein-like ubiquitinated inclusions contain the TAR DNA binding protein, TDP-43 (Neumann et al., 2006; Davidson et al., 2007). Pertinently, the inclusions in SOD1-associated ALS are not TDP-43 immunoreactive (Tan et al., 2007). These latter morphological and immunohistochemical data reinforce the concept that SOD1 and non-SOD1 ALS are separate disorders even though they share a common clinical phenotype. The data, moreover, imply that a role for glial cells, as described in the work of Nagai et al., (2007) and Di Giorgio et al. (2007), may not pertain in the more common forms of ALS that are not associated with SOD1 mutation.

Nonetheless, a potential role for glial cells in non-SOD1 ALS could, perhaps, be tested in ESC-based studies using the Q342X stop codon mutation in the intraflagellar transport protein 74 (IFT74) gene, which has been associated in one family with a frontotemporal dementia and motor neuron disease (FTD+MND) clinical phenotype (Momeni et al., 2006). One patient from this family with this mutation showed ubiquitinated pathological changes within cerebral cortex and brain stem and spinal cord detectable by TDP-43 immunohistochemistry (Cairns et al., 2007). These were typical of those seen in FTD+MND, and in ALS alone (Neumann et al., 2006; Davidson et al., 2007).

References:
Cairns NJ et al (2007) Amer J Pathol (in press).

Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DM. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl). 2007 May;113(5):521-33. Epub 2007 Jan 12. Abstract

Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci. 2007 May;10(5):608-614. Epub 2007 Apr 15. Abstract

Momeni P, Schymick J, Jain S, Cookson MR, Cairns NJ, Greggio E, Greenway MJ, Berger S, Pickering-Brown S, Chio A, Fung HC, Holtzman DM, Huey ED, Wassermann EM, Adamson J, Hutton ML, Rogaeva E, St George-Hyslop P, Rothstein JD, Hardiman O, Grafman J, Singleton A, Hardy J, Traynor BJ. Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD. BMC Neurol. 2006 Dec 13;6:44. Abstract

Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci. 2007 May;10(5):615-622. Epub 2007 Apr 15. Abstract

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. Abstract

Tan CF, Eguchi H, Tagawa A, Onodera O, Iwasaki T, Tsujino A, Nishizawa M, Kakita A, Takahashi H. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol (Berl). 2007 May;113(5):535-42. Epub 2007 Feb 27. Abstract

View all comments by David M.A. Mann

This article elegantly shows the strength of transcriptome analysis for the rapid discovery of a new drug. In this study, the authors identified the therapeutic potential of modulating CD40L in ALS using an animal model.

Through transcriptome analysis, this group identified the upregulation of CD40L-related pathway in three tissues that are all relevant to motor neuron degeneration: muscle, spinal cord, and sciatic nerve. This signaling pathway related to CD40L activation became more prominent as the disease progressed; this finding justifiably led the investigators to test its implication to therapy. The therapeutic potential was tested in mSOD1 mice, and anti-CD40L was found to be effective with respect to both disease onset and progression. The authors compared the results to those observed in inflammatory diseases and, based on Mac-1 expression and T cell activation, suggested that the therapy acts in the animal model of mSOD1 as anti-inflammatory treatment; such a conclusion should be taken with caution, and more so when it comes to clinical translation.

CD40L was...  Read more

This article elegantly shows the strength of transcriptome analysis for the rapid discovery of a new drug. In this study, the authors identified the therapeutic potential of modulating CD40L in ALS using an animal model.

Through transcriptome analysis, this group identified the upregulation of CD40L-related pathway in three tissues that are all relevant to motor neuron degeneration: muscle, spinal cord, and sciatic nerve. This signaling pathway related to CD40L activation became more prominent as the disease progressed; this finding justifiably led the investigators to test its implication to therapy. The therapeutic potential was tested in mSOD1 mice, and anti-CD40L was found to be effective with respect to both disease onset and progression. The authors compared the results to those observed in inflammatory diseases and, based on Mac-1 expression and T cell activation, suggested that the therapy acts in the animal model of mSOD1 as anti-inflammatory treatment; such a conclusion should be taken with caution, and more so when it comes to clinical translation.

CD40L was originally described on T lymphocytes; its expression has since been detected on a wide variety of cells, including platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, as well as non-hematopoietic macrophages. Primarily, in its bound form, CD40L serves as a self-controlling, co-stimulatory molecule; thus, it acts as a mechanism of prevention of unnecessary lymphocyte activation and works at multiple levels. CD40L allows full immune cell activation, prevents anergy or apoptosis, induces differentiation to effector or memory status, sustains cell proliferation, and allows cell-cell crosstalk and cooperation. Therefore, neutralizing CD40L might lead to different effects at different stages of the disease. Moreover, its mechanism of action may be critically affected by the dosing, resulting in an effect suggestive of Dr. Jekyll and Mr. Hyde. This situation is very much reminiscent of minocycline in ALS, which showed similar efficacy in animal models of mSOD1 and failed in human trials. The case of minocycline might represent a general phenomenon with respect to the use of anti-inflammatory therapies in ALS. Such therapies are beneficial in inflammatory diseases such as multiple sclerosis, and, in their relevant animal model, experimental autoimmune encephalomyelitis (EAE). As opposed to ALS, these diseases are inflammatory in their etiology, whereas ALS is characterized by local inflammation, but is not considered an inflammatory disease. Moreover, elevated CD40L in mSOD1 mice might represent beneficial attempts to cope with the disease that are not sufficiently controlled. Therefore, blockage of CD40L may have a beneficial phase/effect/outcome at certain disease stages, but not in a blanket way. Thus, targeting a co-stimulatory molecule as a therapeutic approach may interrupt essential beneficial immune responses in addition to targeting the disease process.

View all comments by Michal Schwartz

Against the backdrop of sometimes disappointing results from genomewide association studies of the transcriptome (GWAS-T), the work by Lincecum and colleagues represents a triumph for this approach. The authors applied transcriptome analysis to the high-copy SOD1 transgenic mouse model of ALS. Importantly, they thoroughly investigated central and peripheral tissues from SOD1 mice at timepoints prior to, during, and after disease onset. Their GWAS-T results pointed to co-stimulatory immune and inflammatory molecules as being centrally associated with ALS-like pathology in this system, and they utilized a sophisticated statistical algorithm to arrive at the CD40-CD40L interaction as a candidate treatment target. They then treated SOD1 mice with a neutralizing CD40L antibody and found benefit by virtually any index of ALS-like disease: the biologic therapy improved body weight maintenance and survival, reduced inflammatory lesions, decreased motor neuron loss, and attenuated expression of immune co-stimulatory genes.

I read this work with enthusiasm and excitement, because over...  Read more

Against the backdrop of sometimes disappointing results from genomewide association studies of the transcriptome (GWAS-T), the work by Lincecum and colleagues represents a triumph for this approach. The authors applied transcriptome analysis to the high-copy SOD1 transgenic mouse model of ALS. Importantly, they thoroughly investigated central and peripheral tissues from SOD1 mice at timepoints prior to, during, and after disease onset. Their GWAS-T results pointed to co-stimulatory immune and inflammatory molecules as being centrally associated with ALS-like pathology in this system, and they utilized a sophisticated statistical algorithm to arrive at the CD40-CD40L interaction as a candidate treatment target. They then treated SOD1 mice with a neutralizing CD40L antibody and found benefit by virtually any index of ALS-like disease: the biologic therapy improved body weight maintenance and survival, reduced inflammatory lesions, decreased motor neuron loss, and attenuated expression of immune co-stimulatory genes.

I read this work with enthusiasm and excitement, because over a decade ago we demonstrated that pharmacologic or genetic blockade of CD40-CD40L interaction mitigated AD-like pathology in transgenic mouse models of the disease. This included reduction of: abnormal tau proteins, cerebral amyloidosis, brain inflammation including gliosis, and behavioral impairment (Tan et al., 1999; Tan et al., 2002). At that time, many in the field of AD research were unwilling to accept that the immune system played any role in the pathogenesis of AD, let alone that immune molecules could be targeted for AD treatment. It is terribly exciting that these authors have extended the concepts that we were exploring vis-à-vis CD40-CD40L in AD to another key neurodegenerative disease: ALS. I hope that the authors are able to successfully translate their findings to the clinical syndrome.

References:
Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science. 1999 Dec 17;286(5448):2352-5. Abstract

Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci. 2002 Dec;5(12):1288-93. Abstract

View all comments by Terrence Town