Butovsky and colleagues have reported that “Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1.” The authors have not shown that glatiramer fights against AD, per se. They do not know whether it will help, harm or be without benefit, because they have not administered it to AD patients. What the authors have done is to administer 5 subcutaneous doses of glatiramer to doubly transgenic APP/PS1 mice and have shown, compared with untreated littermates, less amyloid deposition and less impairment in water maze testing. Their results are comparable to the earlier findings of Frenkel et al. (2006), who administered glatiramer intranasally rather than subcutaneously to transgenic mice. Glatiramer is a mixture of synthetic polypeptides which is currently in use to treat multiple sclerosis. Its mechanism of action is still unclear.

The theory of Butovsky et al. is that the vaccination caused a phenotypic shift in microglial expression from production of the complement receptor CD11b to CD11b/CD11c,...  Read more

Butovsky and colleagues have reported that “Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1.” The authors have not shown that glatiramer fights against AD, per se. They do not know whether it will help, harm or be without benefit, because they have not administered it to AD patients. What the authors have done is to administer 5 subcutaneous doses of glatiramer to doubly transgenic APP/PS1 mice and have shown, compared with untreated littermates, less amyloid deposition and less impairment in water maze testing. Their results are comparable to the earlier findings of Frenkel et al. (2006), who administered glatiramer intranasally rather than subcutaneously to transgenic mice. Glatiramer is a mixture of synthetic polypeptides which is currently in use to treat multiple sclerosis. Its mechanism of action is still unclear.

The theory of Butovsky et al. is that the vaccination caused a phenotypic shift in microglial expression from production of the complement receptor CD11b to CD11b/CD11c, resulting in improved phagocytosis and increased neurogenesis in the transgenic mice. What needs to be emphasized is that transgenic mouse models of AD are not AD itself, and to assume that they are, especially with respect to engaging the adaptive immune system through vaccination, can have severe consequences. This was the case with Elan’s clinical trial for an Aβ vaccine where immune stimulation induced sterile meningitis and cerebral damage in about 5 percent of the cases despite spectacular results in transgenic mice.

There are notable differences in the pathology of AD and transgenic mouse models. For example, in AD there is further processing of the Aβ deposits, converting them into a more insoluble state. In humans there is a higher level of inflammation, caused in large part by vigorous activation of the human complement system by Aβ deposits. Since mouse C1q poorly recognizes human Aβ deposits, complement activation in transgenic mice is minimal. In human AD, there is full activation of the complement system resulting in neuronal destruction by the membrane attack complex. The latter may be the most problematical consequence of immune stimulation in AD.

Butovsky et al. concluded that anti-inflammatory therapy should not be used in AD, and that appropriate immune stimulation should be an effective treatment. If this theory were correct, then individuals taking anti-inflammatory therapy should have a higher risk of developing AD. The opposite is the case. We reviewed 17 epidemiological studies from nine different countries in 1996 (McGeer et al., 1996). All but two showed decreased odds of contracting AD amongst those suffering from arthritis or known to be taking anti-inflammatory drugs. We updated the review in 2006 (McGeer and McGeer, 2006), specifically concentrating on NSAIDs since these are the most widely used anti-inflammatory agents. Twelve of 14 studies showed a decreased risk of developing AD. In addition, eight of eight transgenic animal studies showed a reduction in both Aβ deposits and behavioral deterioration in mice given traditional NSAIDs.

Butovsky et al. noted that their theory “is in line with studies showing that anti-inflammatory drugs, such as cyclooxygenase 2 inhibitors, do not benefit AD.” This is certainly true, since four clinical trials of selective COX-2 inhibitors have failed. But COX-2 is a questionable target for the brain. It is one of the few organs of the body which constitutively expresses this enzyme, which is most highly concentrated in pyramidal neurons. Presumably, there is a significant physiological function associated with this high level of expression, and blocking prostaglandin production in pyramidal neurons could have negative consequences. Moreover, COX-2 inhibitors have been too recently introduced for any epidemiological evidence to have accumulated showing whether their long-term use increases or reduces the risk of developing AD. However, COX-2 inhibitors have been tried without benefit in transgenic animal studies (see Kukar et al., 2005).

It is not beyond the realm of possibility that ways can be found in humans of stimulating microglia to phagocytose while blunting the self-destruction they cause by excessive output of oxygen free radicals, prostaglandins, inflammatory cytokines, proteases, complement proteins, and other toxic materials. But whether or how this might be done is still unknown. Butovsky et al. have suggested a possibility which certainly deserves further exploration. We can hope they have set investigators on a promising trail, but direct application of their theory to AD cases should be approached with caution.

View all comments by P.L. McGeer

This article, resulting from the collaboration between both the University of Washington and the University of California, Davis, provides robust new evidence that further implicates excess TNFα in the pathogenesis of Alzheimer disease. This article joins an increasing body of evidence that began in the early 1990s, with the work of Howard Fillit (Fillit et al, 1991), and the multiple publications from the Vancouver group led by McGeers (Klegeris et al., 1997). It has continued with multiple publications in 2006 (see references), which suggest that TNFα plays a central role in the pathogenesis of Alzheimer disease. A search in Google Scholar of "TNF Alzheimer's" now yields over 4,000 citations.

Ramos and his co-authors conclude: "The data support that therapeutic strategies designed to reduce TNFα protein production or activity might be a valuable treatment for AD." There is an urgent need for the Alzheimer research community to take note of these findings and initiate...  Read more

This article, resulting from the collaboration between both the University of Washington and the University of California, Davis, provides robust new evidence that further implicates excess TNFα in the pathogenesis of Alzheimer disease. This article joins an increasing body of evidence that began in the early 1990s, with the work of Howard Fillit (Fillit et al, 1991), and the multiple publications from the Vancouver group led by McGeers (Klegeris et al., 1997). It has continued with multiple publications in 2006 (see references), which suggest that TNFα plays a central role in the pathogenesis of Alzheimer disease. A search in Google Scholar of "TNF Alzheimer's" now yields over 4,000 citations.

Ramos and his co-authors conclude: "The data support that therapeutic strategies designed to reduce TNFα protein production or activity might be a valuable treatment for AD." There is an urgent need for the Alzheimer research community to take note of these findings and initiate further study of this highly promising approach to Alzheimer disease treatment. This is particularly true in view of the availability of a potent and selective biologic inhibitor of TNFα, etanercept, and a new method of perispinal delivery which may enhance its therapeutic activity for CNS applications (see Tobinick et al., 2006). (Please, of course, see my accompanying disclosure.)

References:
1. Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, Sonobe Y, Mizuno T, Suzumura A. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem, 2006. 281(30): p. 21362-8. Abstract

2. Ranaivo, H.R., et al., Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci, 2006. 26(2): p. 662-70.

3. Ramos EM, Lin MT, Larson EB, Maezawa I, Tseng LH, Edwards KL, Schellenberg GD, Hansen JA, Kukull WA, Jin LW. Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol, 2006. 63(8): p. 1165-9. Abstract

4. Meme W, Calvo CF, Froger N, Ezan P, Amigou E, Koulakoff A, Giaume C. Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid. Faseb J, 2006. 20(3): p. 494-6. Abstract

5. Lio D, Annoni G, Licastro F, Crivello A, Forte GI, Scola L, Colonna-Romano G, Candore G, Arosio B, Galimberti L, Vergani C, Caruso C. Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer's disease. Mech Ageing Dev, 2006. 127(6): p. 567-71. Abstract

6. Craft JM, Watterson DM, Van Eldik LJ. Human amyloid beta-induced neuroinflammation is an early event in neurodegeneration. Glia, 2006. 53(5): p. 484-90. Abstract

7. Zuliani G, Ranzini M, Guerra G, Rossi L, Munari MR, Zurlo A, Volpato S, Atti AR, Ble A, Fellin R. Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res, 2006. Abstract

8. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha Modulation for Treatment of Alzheimer's Disease: A 6-Month Pilot Study. MedGenMed, 2006. 8(2): p. 25. Abstract

9. Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M. Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging, 2006. Abstract

View all comments by Edward Tobinick

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

The paper from Joseph El Khoury and colleagues presents convincing evidence that the absence of activated microglia is detrimental in the Tg2576 model. On the surface, from our study in J. Neuroscience, one may conclude that microglial activation is harmful. It likely depends on the context of how you are viewing the problem. Early on, microglial activation may be helpful by facilitating clearance of Aβ from brain; in their absence more Aβ accumulates (El Khoury). On the other hand, if Aβ is not cleared and microglia remain activated, this may lead to the chronic neuroinflammation and behavioral deficits that we observed in our model.

Another caveat that we must all recognize is what are the specific features of the models we work with. Each has its own strengths and weaknesses for studying specific aspects of Aβ pathology. For example, the widely used Tg2576 mouse expresses high amounts of Swedish mutant human APP in many cell types, producing high amounts of wild-type Aβ peptides and parenchymal amyloid plaques. The Tg-SwDI mouse expresses low...  Read more

The paper from Joseph El Khoury and colleagues presents convincing evidence that the absence of activated microglia is detrimental in the Tg2576 model. On the surface, from our study in J. Neuroscience, one may conclude that microglial activation is harmful. It likely depends on the context of how you are viewing the problem. Early on, microglial activation may be helpful by facilitating clearance of Aβ from brain; in their absence more Aβ accumulates (El Khoury). On the other hand, if Aβ is not cleared and microglia remain activated, this may lead to the chronic neuroinflammation and behavioral deficits that we observed in our model.

Another caveat that we must all recognize is what are the specific features of the models we work with. Each has its own strengths and weaknesses for studying specific aspects of Aβ pathology. For example, the widely used Tg2576 mouse expresses high amounts of Swedish mutant human APP in many cell types, producing high amounts of wild-type Aβ peptides and parenchymal amyloid plaques. The Tg-SwDI mouse expresses low levels of Swedish/Dutch/Iowa mutant human APP only in neurons producing low levels of vasculotropic Dutch/Iowa mutant Aβ peptides and microvascular amyloid deposits. In light of these differences in the models, some variations in results may be attributed to the sites of amyloid deposition and possibly due to differences in microglial responses to wild-type and vasculotropic mutant Aβ peptides and amyloid deposits.

View all comments by William Van Nostrand

El Khoury et al. have produced a dataset that adds to those indicating a beneficial role for monocytic phagocytes (either activated microglia or hematogenous macrophages) with respect to the development of Alzheimer-related pathology. Some data have indicated that inflammation-related events elaborated by microglia contribute to AD pathology. This includes the overexpression of interleukin-1-β in APP-transgenic mouse models of AD, as well as attenuation of Aβ accumulation in these mice by anti-inflammatory agents such as ibuprofen and, more recently, minocycline (see Fan et al., 2007). But beginning with paradigms in which such mice are immunized against Aβ, increasing evidence has suggested that monocyte-derived cells can help to clear Aβ from the brain through phagocytosis and/or expression of Aβ-degrading proteases. For instance, Morgan and colleagues have shown that injection of the powerful inflammatory agent lipopolysaccharide into APP-transgenic mice results in Aβ clearance (DiCarlo et al., 2006), and the clearance or prevention of Aβ...  Read more

El Khoury et al. have produced a dataset that adds to those indicating a beneficial role for monocytic phagocytes (either activated microglia or hematogenous macrophages) with respect to the development of Alzheimer-related pathology. Some data have indicated that inflammation-related events elaborated by microglia contribute to AD pathology. This includes the overexpression of interleukin-1-β in APP-transgenic mouse models of AD, as well as attenuation of Aβ accumulation in these mice by anti-inflammatory agents such as ibuprofen and, more recently, minocycline (see Fan et al., 2007). But beginning with paradigms in which such mice are immunized against Aβ, increasing evidence has suggested that monocyte-derived cells can help to clear Aβ from the brain through phagocytosis and/or expression of Aβ-degrading proteases. For instance, Morgan and colleagues have shown that injection of the powerful inflammatory agent lipopolysaccharide into APP-transgenic mice results in Aβ clearance (DiCarlo et al., 2006), and the clearance or prevention of Aβ deposits in immunized mice is associated with some signs that microglia are more active.

An important question has been whether these beneficial roles of monocytic phagocytes are operative in the basal condition (and eventually overwhelmed in the development of disease) or are instead induced only by extraordinary manipulation, such as immunization or injections of lipopolysaccharide. El Khoury’s approach was to remove or reduce a chemokine receptor (CCR2) responsible for trafficking microglia and/or peripheral macrophages to sites of inflammation, which would include amyloid plaques in the APP transgenic mice. The resulting increase in Aβ accumulation (both soluble and deposits), coupled with an absence of the accumulation of monocytic phagocytes that normally arises in APP transgenics, suggests that monocyte-derived cells tonically participate in the removal of Aβ; microglia from the CCR2-knockout mice still reacted to Aβ in culture. This specific requirement for chemotaxis, then, is consistent with recent studies showing the homing of bone marrow-derived monocytic cells to plaques in APP transgenics (Simard et al., 2006). Microglia are so extensively distributed throughout the cortex that one should imagine they scarcely need to migrate if they were the primary mediators of Aβ clearance.

Of course, the caveat that an APP transgenic mouse is not a human with AD goes without saying. And that may be most relevant to the interpretation of what happens downstream of Aβ clearance. El Khoury et al. reported a decrease in lifespan in the CCR2-knockout animals, but this may have been due to cerebrovascular hemorrhage. It is possible that well-intentioned clearance of Aβ, regardless of how successful, may produce byproducts that interfere with neurophysiology. To wit, the application of the anti-inflammatory antibiotic minocycline by Fan et al. protected against behavioral deficits in APP transgenic mice without altering Aβ levels or deposition, and ibuprofen treatment is associated with a decrease in a marker of apoptosis per plaque rather than a reduction in plaques themselves (Lim et al., 2001). Thus, strategies aimed at optimizing the impact of inflammatory processes or monocytic phagocytes on AD pathogenesis should take into account the potential requirement of a balance between the benefits of Aβ clearance and the maladaptive consequences of inflammatory sequelae on neuronal function and viability.

It is somewhat unfortunate that El Khoury et al. utilized an APP-transgenic strain that has a mixed genetic background (SJL x C57BL/6). Aβ deposition is notoriously strain-dependent, with the relevant alleles remaining unknown. Any cross of a mixed background creates the opportunity for genetic variability in the progeny, even in littermates. This concern can be mitigated by analyzing sufficient numbers. El Khoury et al. used as few as three or four animals per group, which seems low except for the fact that techniques were applied which precluded the use of the same animals for some of the techniques (e.g., immunohistochemistry vs. FACS); thus, the true numbers of animals over which dramatic differences were seen was actually six or seven per genotype.

References:
Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE. Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci. 2007 Mar 21;27(12):3057-63. Abstract

DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan D. Intrahippocampal LPS injections reduce Aβ load in APP+PS1 transgenic mice. Neurobiol Aging. 2001 Nov-Dec;22(6):1007-12. Abstract

Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron. 2006 Feb 16;49(4):489-502. Abstract

Lim GP, Yang F, Chu T, Gahtan E, Ubeda O, Beech W, Overmier JB, Hsiao-Ashe K, Frautschy SA, Cole GM. Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging. 2001 Nov-Dec;22(6):983-91. Abstract

View all comments by Steve Barger

It is odd that an effect was noted by El Khoury et al. in a Ccr2 knockout. Cedric Raines showed in a landmark paper that Ccr2 was so redundant that it made no impact on trafficking of monocyte-related cells in EAE (experimental autoimmune encephalomyelitis).

References:
Gaupp S, Pitt D, Kuziel WA, Cannella B, Raine CS. Experimental autoimmune encephalomyelitis (EAE) in CCR2(-/-) mice: susceptibility in multiple strains. Am J Pathol. 2003;162:139-50. Abstract

View all comments by Bo Hu

The report by El Khoury and colleagues shows that recruitment of macrophage-like cells to the brains of Tg2576 mice via Ccr2 plays an important role in limiting AD-like pathology. This is a very interesting finding and extends the work of Stalder et al. (2005), who noted the presence of round, non-process-bearing, macrophage-like cells in APP23 mice with appreciable amyloid deposits.

El Khoury et al. have gone further by establishing that Ccr2-dependent recruitment of microglia/macrophage-like cells is important in limiting progression of cerebral amyloidosis. If taken to the logical endpoint, this would mean that microglia and/or macrophages serve to limit amyloidosis by phagocytosing/clearing amyloid deposits in AD mice in the absence of genetic manipulation (and perhaps something similar may occur in AD patients). However, careful 3D reconstruction of microglia and amyloid in APP23 or Tg2576 mice fails to show this (Stalder et al., 2001; Wegiel et al., 2004).

An alternate explanation is that microglia/macrophages secrete a soluble factor (e.g., a cytokine or...  Read more

The report by El Khoury and colleagues shows that recruitment of macrophage-like cells to the brains of Tg2576 mice via Ccr2 plays an important role in limiting AD-like pathology. This is a very interesting finding and extends the work of Stalder et al. (2005), who noted the presence of round, non-process-bearing, macrophage-like cells in APP23 mice with appreciable amyloid deposits.

El Khoury et al. have gone further by establishing that Ccr2-dependent recruitment of microglia/macrophage-like cells is important in limiting progression of cerebral amyloidosis. If taken to the logical endpoint, this would mean that microglia and/or macrophages serve to limit amyloidosis by phagocytosing/clearing amyloid deposits in AD mice in the absence of genetic manipulation (and perhaps something similar may occur in AD patients). However, careful 3D reconstruction of microglia and amyloid in APP23 or Tg2576 mice fails to show this (Stalder et al., 2001; Wegiel et al., 2004).

An alternate explanation is that microglia/macrophages secrete a soluble factor (e.g., a cytokine or protease) that limits cerebral amyloidosis. Yet, the converse—that reactive glia produce acute phase reactants/cytokines such as ApoE, ACT and IL-1 that promote amyloidosis—has been shown (Potter et al., 2001; Nilsson et al., 2001). In light of these reports, what is the authors’ take on the mechanism responsible for their finding?

El Khoury et al. also report that Ccr2 deletion limits the lifespan of Tg2576 animals, and suggest that there is a connection between increased AD-like pathology in Ccr2-deficient Tg2576 mice and their premature death. This conclusion should be taken with caution. Although not often pointed out, Tg2576 mice actually overexpress the mutant human APP transgene in regions other than the brain (for example, peripheral vascular smooth muscle cells and endothelial cells), and it is well-established that transgene-derived Aβ is easily detected systemically in these mice, so early death of Ccr2-deficient Tg2576 mice may be CNS-independent.

The paper by Fan and colleagues presents an interesting set of results that suggest dampening microglial activation via minocycline treatment is beneficial in their mouse model of vascular amyloidosis. Interestingly, they found reduction in “activated” microglia that corresponded with mitigation of behavioral impairment. Their results fit well with the work of Greg Cole’s group, who showed that treatment of Tg2576 mice with the non-steroidal anti-inflammatory drug (NSAID) ibuprofen or the naturally occurring NSAID curcumin reduces microglial activation concomitant with reduced cerebral amyloidosis and behavioral impairment (Lim et al., 2000; Lim et al, 2001a; Lim et al., 2001b). Fan and colleagues’ data also fit well with our previous results showing that genetic or pharmacologic interruption of CD40-CD40 ligand interaction mitigates microglial activation in response to Aβ peptides, and reduces microgliosis, cerebral amyloidosis, and behavioral impairment in AD mouse models (Tan, Town et al., 1999; Tan, Town et al., 2002; Town et al., 2001; Todd Roach et al., 2004).

When taken together, the studies suggest that “activation” of microglia/macrophages is not simply one phenotype. We have suggested that these innate immune cells may respond with a range of responses from pro-phagocytic/anti-inflammatory to anti-phagocytic/proinflammatory (Town et al., 2005). Understanding the molecular underpinnings of these various responses of microglia/macrophages will likely be key in targeting these cells for therapeutic intervention in neurodegenerative diseases (particularly AD).

References:
El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Medicine. 2007, March 11. Advanced online publication. Abstract

Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE. Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci. 2007;27(12):3057-63. Abstract

Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. Journal of Neuroscience. 2000 Aug 1;20(15):5709-14. Abstract

Lim GP, Yang F, Chu T, Gahtan E, Ubeda O, Beech W, Overmier JB, Hsiao-Ashec K, Frautschy SA, Cole GM. Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiology of Aging. 2001;22(6):983-91. Abstract

Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. Journal of Neuroscience. 2001;21(21):8370-7. Abstract

Nilsson LN, Bales KR, DiCarlo G, Gordon MN, Morgan D, Paul SM, Potter H. Alpha-1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease. Journal of Neuroscience. 2001;21(5):1444-51. Abstract

Potter H, Wefes IM, Nilsson LN. The inflammation-induced pathological chaperones ACT and apo-E are necessary catalysts of Alzheimer amyloid formation. Neurobiology of Aging. 2001;22(6):923-30. Abstract

Stalder M, Deller T, Staufenbiel M, Jucker M. 3D-Reconstruction of microglia and amyloid in APP23 transgenic mice: no evidence of intracellular amyloid. Neurobiology of Aging. 2001;22(3):427-34. Abstract

Stalder AK, Ermini F, Bondolfi L, Krenger W, Burbach GJ, Deller T, Coomaraswamy J, Staufenbiel M, Landmann R, Jucker M. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. Journal of Neuroscience. 2005;25(48):11125-32. Abstract

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;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. Nature Neuroscience. 2002;5(12):1288-93. Abstract

Todd Roach J, Volmar CH, Dwivedi S, Town T, Crescentini R, Crawford F, Tan J, Mullan M. Behavioral effects of CD40-CD40L pathway disruption in aged PSAPP mice. Brain Research. 2004;1015(1-2):161-8. Abstract

Town T, Tan J, Mullan M. CD40 signaling and Alzheimer's disease pathogenesis. Neurochemistry International. 2001;39(5-6):371-80. Abstract

Town T, Nikolic V, Tan J. The microglial "activation" continuum: from innate to adaptive responses. Journal of Neuroinflammation. 2005;2:24. Abstract

Wegiel J, Imaki H, Wang KC, Wegiel J, Rubenstein R. Cells of monocyte/microglial lineage are involved in both microvessel amyloidosis and fibrillar plaque formation in APPsw tg mice. Brain Research. 2004;1022(1-2):19-29. Abstract

View all comments by Terrence Town