Schwartz M.
Macrophages and microglia in central nervous system injury: are they helpful or harmful?.
J Cereb Blood Flow Metab. 2003 Apr;23(4):385-94.
PubMed.
This interesting review proposes that, under certain circumstances, microglia may enhance rather than retard neuronal survival. This hypothesis is contrary to the view held by many AD researchers that microglia have an entirely negative effect on neuronal survival and function in AD. The authors correctly point out that much of the evidence for microglial neurotoxicity in AD is based on "guilt by association," namely, immunohistochemical studies showing activated microglia expressing cytokines and other inflammatory markers in proximity to neuritic plaques. However, many of the cytokines expressed by microglia can have neuroprotective as well as neurotoxic effects, depending on conditions (for another exposition of this point of view, see CS Raine, 2000).
In comparison with phenotypic studies of microglia in AD brain, there are far fewer studies of neuronal-microglial interactions in experimental systems designed to model AD that could more directly address the effects of activated microglia. Schwartz reviews work showing that in model systems involving T cell-microglial interactions, which more closely approximate MS than AD, microglia can have neuroprotective effects. As the author advocates, there is need for more research on the potentially positive effects of microglia in a variety of neurologic disorders.
A related issue not directly addressed by Schwartz is the role of microglia in the therapeutic effects as well as the adverse events associated with amyloid-β immunization. First, there is the possibility advocated by Bard and colleagues that microglia may clear opsonized amyloid-β after immunization of transgenic mice, which in turn could result in improved neuronal function and survival. If true, this would mean that microglia can be manipulated in the living CNS to perform functions that have a net positive effect. On the other hand, neuropathologic data showing T cell infiltrates (which could promote a potentially harmful microglial response) and white matter macrophage accumulation after amyloid-β immunization in humans raise concerns about the role of microglia in lethal inflammatory adverse events. For a further discussion of this issue, see Weiner and Selkoe, 2002.
Another related issue is the role of microglia in therapeutic response to antiinflammatory medications in AD. Most antiinflammatory medications suppress microglial activation, which could have a positive effect if indeed microglial activation in AD has a negative effect. Although epidemiologic data suggest that a long history of antiinflammatory use reduces risk for AD, short-term treatment of AD with these agents has been disappointing thus far. As suggested by Raine, perhaps these medications could interfere with certain potentially restorative functions of microglia during the later stages of AD.
My guess is that microglia will be found to have both positive as well as negative functions in AD and in AD therapeutics. The view that microglia have an entirely negative role in neurodegeneration may be outdated.
References:
Raine CS.
Inflammation in Alzheimer's disease: a view from the periphery.
Neurobiol Aging. 2000 May-Jun;21(3):437-40; discussion 451-3.
PubMed.
Weiner HL, Selkoe DJ.
Inflammation and therapeutic vaccination in CNS diseases.
Nature. 2002 Dec 19-26;420(6917):879-84.
PubMed.
Comments
Stanford University School of Medicine
This interesting review proposes that, under certain circumstances, microglia may enhance rather than retard neuronal survival. This hypothesis is contrary to the view held by many AD researchers that microglia have an entirely negative effect on neuronal survival and function in AD. The authors correctly point out that much of the evidence for microglial neurotoxicity in AD is based on "guilt by association," namely, immunohistochemical studies showing activated microglia expressing cytokines and other inflammatory markers in proximity to neuritic plaques. However, many of the cytokines expressed by microglia can have neuroprotective as well as neurotoxic effects, depending on conditions (for another exposition of this point of view, see CS Raine, 2000).
In comparison with phenotypic studies of microglia in AD brain, there are far fewer studies of neuronal-microglial interactions in experimental systems designed to model AD that could more directly address the effects of activated microglia. Schwartz reviews work showing that in model systems involving T cell-microglial interactions, which more closely approximate MS than AD, microglia can have neuroprotective effects. As the author advocates, there is need for more research on the potentially positive effects of microglia in a variety of neurologic disorders.
A related issue not directly addressed by Schwartz is the role of microglia in the therapeutic effects as well as the adverse events associated with amyloid-β immunization. First, there is the possibility advocated by Bard and colleagues that microglia may clear opsonized amyloid-β after immunization of transgenic mice, which in turn could result in improved neuronal function and survival. If true, this would mean that microglia can be manipulated in the living CNS to perform functions that have a net positive effect. On the other hand, neuropathologic data showing T cell infiltrates (which could promote a potentially harmful microglial response) and white matter macrophage accumulation after amyloid-β immunization in humans raise concerns about the role of microglia in lethal inflammatory adverse events. For a further discussion of this issue, see Weiner and Selkoe, 2002.
Another related issue is the role of microglia in therapeutic response to antiinflammatory medications in AD. Most antiinflammatory medications suppress microglial activation, which could have a positive effect if indeed microglial activation in AD has a negative effect. Although epidemiologic data suggest that a long history of antiinflammatory use reduces risk for AD, short-term treatment of AD with these agents has been disappointing thus far. As suggested by Raine, perhaps these medications could interfere with certain potentially restorative functions of microglia during the later stages of AD.
My guess is that microglia will be found to have both positive as well as negative functions in AD and in AD therapeutics. The view that microglia have an entirely negative role in neurodegeneration may be outdated.
References:
Raine CS. Inflammation in Alzheimer's disease: a view from the periphery. Neurobiol Aging. 2000 May-Jun;21(3):437-40; discussion 451-3. PubMed.
Weiner HL, Selkoe DJ. Inflammation and therapeutic vaccination in CNS diseases. Nature. 2002 Dec 19-26;420(6917):879-84. PubMed.
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