0022-3565/03/3041-1–7 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 304, No. 1 U.S. Government work not protected by U.S. copyright 35048/1026111 JPET 304:1–7, 2003 Printed in U.S.A. Role of Microglia in Inflammation-Mediated Neurodegenerative Diseases: Mechanisms and Strategies for Therapeutic Intervention BIN LIU and JAU-SHYONG HONG Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina Received June 6, 2002; accepted August 13, 2002 ABSTRACT Evidence from postmortem analysis implicates the involvement of proinflammatory and neurotoxic factors that are believed to of microglia in the neurodegenerative process of several de- induce and/or exacerbate neurodegeneration. In this article, we generative neurological diseases, including Alzheimer’s dis- summarize recent advances on the study of the role of micro- ease and Parkinson’s disease. It remains to be determined, glia based on findings from animal and cell culture models in however, whether microglial activation plays a role in the initi- the pathogenesis of neurodegenerative diseases, with particu- ation stage of disease progression or occurs merely as a re- lar emphasis on Parkinson’s disease. In addition, we also dis- sponse to neuronal death. Activated microglia secrete a variety cuss novel approaches to potential therapeutic strategies. Microglia logical changes from resting ramified cells to activated amoe- boid microglia (Kreutzberg, 1996). Microglia are considered the resident immune cells of the Besides morphological changes and surface molecule up- central nervous system (CNS). Since the initial comprehen- regulation, activated microglia secrete a host of soluble fac- sive description of microglia by del Rio-Hortega in 1932, the tors. A number of these factors, such as the glia-derived exact origin of microglia remains the subject of debate. Nu- neurotrophic factor, are potentially beneficial to the survival merous studies in the last three decades, however, have generally supported the view that microglia derive from me- of neurons, reminiscence of the neuroprotective role played sodermal precursor cells of possibly hematopoietic lineage by activated astrocytes, another major type of glial cells in that enter the brain during the embryonic and early postna- the brain (Aloisi, 1999). The majority of factors produced by tal phases of development (for reviews, see Barron, 1995; activated microglia, however, are proinflammatory and neu- Cuadros and Navascues, 1998). During brain remodeling and rotoxic. These include the cytokines tumor necrosis factor-␣ maturation, microglia are believed to assist in the clearance (TNF␣) and interleukin-1␤ (IL-1␤), free radicals such as ni- of cells deemed for elimination through programmed cell tric oxide (NO) and superoxide, fatty acid metabolites such as death. In the mature brain and under physiological condi- eicosanoids, and quinolinic acid. Studies using cell culture tions, resting microglia adopt the characteristic ramified and animal models have demonstrated that excessive quan- morphological appearance and serve the role of immune sur- tities of individual factors produced by activated microglia veillance and host defense. Microglia, however, are particu- can be deleterious to neurons (Boje and Arora, 1992; Chao et larly sensitive to changes in their microenvironment and al., 1992; McGuire et al., 2001). Furthermore, individual readily become activated in response to infection or injury. factors often work in concert to induce neurodegeneration. Activated microglia up-regulate a variety of surface recep- For example, Chao et al. (1995) reported that the combina- tors, including the major histocompatibility complex and tion of IL-1␤ and TNF␣, but not either cytokine alone, in- complement receptors. They also undergo dramatic morpho- duced the degeneration of cortical neurons. Jeohn and col- leagues (1998) have shown that the combination of IL-1␤, TNF␣, and interferon-␥ work in synergy to induce degener- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. ation of cortical neurons. Recently, Xie et al. (2002) showed DOI: 10.1124/jpet.102.035048. that peroxynitrite, possibly a product of superoxide and NO, ABBREVIATIONS: CNS, central nervous system; TNF␣, tumor necrosis factor-␣; IL-1␤, interleukin-1␤; NO, nitric oxide; LPS, lipopolysaccharide; AD, Alzheimer’s disease; PD, Parkinson’s disease; SN, substantia nigra; HIV, human immunodeficiency virus; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; A␤, beta amyloid peptide; ROS, reactive oxygen species. 1 2 Liu and Hong is a major mediator of neurotoxicity induced by lipopolysac- neurons. One of the best-studied agents in this group may be charide (LPS) or ␤-amyloid peptide (1-42). the bacterial cell wall endotoxin LPS. LPS is a widely used and powerful tool for the activation of microglia and of pe- Evidence for the Involvement of Microglia in ripheral immune cells. Although LPS has no known direct Neurodegenerative Diseases toxic effect on neurons, it activates microglia to release a host of neurotoxic factors to induce neuronal death (Bronstein et The involvement of microglial activation in the pathogen- al., 1995; Araki et al., 2001; Liu et al., 2002c). In contrast to esis of several neurodegenerative diseases was initially pos- the action of LPS, certain agents are known to have a direct tulated based on the postmortem analysis of the brains of neurotoxic effect. Two experimental neurotoxins for dopami- patients with Alzheimer’s disease (AD) and Parkinson’s dis- nergic neurons, namely 1-methyl-4-phenyl-1,2,3,6-tetrahy- ease (PD). For instance, reactive microglia were found to dropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), are colocalize with neuritic plaques in the cortical region of AD good examples. Direct damage to neurons by these agents brains (Rogers et al., 1988). In PD brains, large numbers of causes reactive gliosis. Activation of microglia in turn exac- human leukocyte antigen (HLA-DR)-positive reactive micro- erbates the neurodegenerative process. For example, mice glia were found in the substantia nigra (SN), a region in lacking inducible nitric oxide synthase activity are resistant which the degeneration of dopaminergic neurons was most to MPTP-induced lesions and inhibition of microglial activa- prominent (McGeer et al., 1988). In addition to AD and PD, tion reduces MPTP neurotoxicity (Itzhak et al., 1999; Libera- results from both in vivo and in vitro studies have since tore et al., 1999; Dehmer et al., 2000; Du et al., 2001; Wu et established an association of microglial activation with the al., 2002). In the striatum and SN of 6-OHDA lesioned rat pathogenesis of human immunodeficiency virus (HIV) ac- brains, prominent microglial activation was detectable weeks quired immunodeficiency syndrome dementia complex, after the lesion (Cicchetti et al., 2002). amyotrophic lateral sclerosis, multiple sclerosis, and prion- In addition to the direct and indirect toxins mentioned related diseases (Dickson et al., 1993; Raine, 1994; Brown, 2001). above, it is interesting to note that another group of agents that are known to be associated with various neurodegenera- tive diseases exhibit a “mixed mode” mechanism of neurotox- Multiple Pathways Leading to Microglial icity. These include ␤-amyloid peptides (A␤), HIV coat pro- Activation tein gp120, prion protein-derived peptides, and the pesticide It is now generally accepted that microglia contribute to rotenone (Fig. 1). Previous reports have generally attributed the neurodegenerative process through the release of a vari- their neurotoxicity to a direct impact on neurons. Recent ety of neurotoxic factors that exacerbate the degeneration of studies from several laboratories, however, have revealed neurons. It remains to be determined, however, what triggers that activation of microglia and the subsequent release of microglial activation in these various disorders. Important neurotoxic factors contribute to their neurotoxicity. For ex- clues relevant to understanding the pathogenesis of degen- ample, the potency of A␤ (1-42)-induced neurotoxicity on erative neurological disorders can be obtained by comparing cultured cortical and mesencephalic neurons increased by the mode of action of a wide spectrum of potentially neuro- severalfold in the presence of microglia (Qin et al., 2002). The toxic agents (Fig. 1). At one end of the spectrum are those enhanced neurotoxicity of A␤ (1-42) was attributed primarily agents that appear to be totally incapable of directly killing to the activation of microglia and subsequent release of the Fig. 1. A simplified classification of three types of potentially neuro- toxic agents. Microglial Activation and Neurodegeneration 3 superoxide free radical. In the case of rotenone, which was (Greenamyre et al., 1999). Therefore, it is logical to infer that initially thought to damage dopaminergic neurons by inhib- activation of microglia, as a consequence of neuronal injury iting mitochondrial complex I activity, the presence of micro- or infection, represents a risk factor that may trigger the glia significantly enhanced its neurotoxicity, and the gener- onset of a cascade of events leading to a progressive degen- ation of oxygen free radicals appeared to underlie this eration of dopaminergic neurons. increased toxicity (Gao et al., 2002a). Similarly, the