Review article
The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis

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Abstract

Macrophage/microglia (M∅) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Astrocytes, as a significant component of the blood–brain barrier, behave as one of the immune effecter cells in the CNS as well. However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Interactions of the immune system, M∅, and astrocytes result in altered production of neurotoxins and neurotrophins by these cells. These effects alter the neuronal structure and function during pathogenesis of HIV-1-associated dementia (HAD), Alzheimer disease (AD), and multiple sclerosis (MS). HAD primarily involves subcortical gray matter, and both HAD and MS affect sub-cortical white matter. AD is a cortical disease. The process of M∅ and astrocytes activation leading to neurotoxicity share similarities among the three diseases. Human Immunodeficiency Virus (HIV)-1-infected M∅ are involved in the pathogenesis of HAD and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). In AD, M∅s produce these molecules and are activated by β-amyloid proteins and related oligopeptides. Demyelination in MS involves M∅ that become lipid laden, spurred by several possible antigens. In these three diseases, cytokine/chemokine communications between M∅ and astrocytes occur and are involved in the balance of protective and destructive actions by these cells. This review describes the role of M∅ and astrocytes in the pathogenesis of these three progressive neurological diseases, examining both beneficent and deleterious effects in each disease.

Section snippets

Role of M∅ and astrocytes in neurological disorders

Macrophage/microglia (M∅) constitute 12% of the cells in the central nervous system (CNS) [1]. These cells are primary immune effector cells of the CNS. Their functions include phagocytosis, antigen presentation, and production and release of cytokines, eicosanoids, complement components, and excitatory amino acids such as glutamate, oxidative radicals, and nitric oxide [2], [3], [4]. Three states of M∅ have been identified based on developmental and pathophysiologic studies: (i) the resting,

Role of M∅ and astrocytes in HIV-1-associated dementia

HAD is the leading cause of dementia in individuals aged 20 to 59 years [16]. Symptomatic HIV-1 infection of the brain may present with HAD, HIV-1-associated minor cognitive/motor disorder, or other neuropsychiatric and neurologic disorders (Table 1). HAD, a subcortical dementia, is characterized by progressive motor abnormalities (tremor, gait ataxia, and loss of fine motor movements), cognitive impairments (mental slowing, forgetfulness, and poor concentration), and behavioral disorders

Alzheimer disease

Alzheimer disease (AD) is the most frequent cause of dementia and manifests with progressive memory impairment, language disorders, problems with judgment, problem solving, planning, abstract thought, apraxia, and deficits in visual function (Table 1) [85], [86], [87]. Several lines of evidence suggest that β-amyloid is involved in the neuro-degenerative cascade of AD [88]. The amyloid burden found in postmortem brain tissue of AD patients is positively correlated with severity of dementia in

Multiple sclerosis

Multiple sclerosis (MS) is the major cause of neurological disability among young adults. MS follows a recurrent and/or progressive course and is associated with immunologic aberrations that involve several cell groups. Clinically, MS manifests with fatigue and disturbed function in sensory, motor, bladder and bowel, cerebellar, brainstem, optic nerves, and cognitive realms (Table 1). MS is an inflammatory disease of the CNS white matter that uncommonly causes dementia. Lymphocytes and

The balance between M∅ and astrocytes and their effect on Th1/Th2

T helper 1 (Th1) and T helper 2 cells (Th2) may be regarded as polarized forms of immune response. The mechanisms that regulate the balance of Th1 and Th2 cells, including cytokines, affect the outcome of several diseases. For example, IL-12, which is produced by M∅, is crucial in the development of an immune response, particularly in inducing the differentiation of Th precursor cells into the Th1 phenotype [143], whereas IL-4 promotes expansion of Th2 cells. In MS, a possible balance between

M∅, astrocytes, and their effect on effecters cells and CNS demyelination

Activation of M∅ during the inflammatory process of MS contributes directly to myelin damage through several mechanisms including production of cytokines, metalloproteinases, production of free radicals, and phagocytosis.

Reactive astrocytes support axonal regrowth by expressing neurotrophic factors and cytokines [145]. These cells secrete nerve growth factor (NGF), which circumvents the development of EAE [126], express functional IL-4 receptors, and secrete NGF upon exposure to IL-4 [146].

Conclusion

Cascades of inflammatory processes lead to neurodegeneration in all three of the neurological diseases discussed. The initial step in each disease differs. HAD is secondary to infection with HIV-1, although the exact causes of AD and MS remain to be established. A common feature among the three diseases is the interactions of M∅ and astrocytes. These interactions play significant roles in the initiation and continuation of the neurodegenerative process in each disease. In HAD, M∅ and astrocytes

Acknowledgements

We thank Drs. W.G. Bradley, C.K. Petito and K. Goodkin for discussions. This work was supported in part by NIH Grants DA 04787, DA 07909, DA 12580, DA 14533, AG 19952, NS 39177, NS 41205 and NS 31488.

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