Neurodegenerative disease and the neuroimmune axis (Alzheimer's and Parkinson's disease, and viral infections)

Abstract

The appearance of activated immune cells and the accumulation of inflammation-associated proteins are common phenomena associated with neurodegenerative diseases. These inflammatory components of central nervous system (CNS) diseases have most often been described in the context of an immune response to damage and cell loss already occurring in the affected brain area. There has, however, been a renewed interest in how the neuroimmune axis might itself be involved in the etiology of these neurodegenerative diseases, particularly in cases involving slow, chronic, progressive neuropathology. This review addresses immune activation in Alzheimer's, Parkinson's, and brain viral infections that may be causative of, rather than responsive to, the observed neuronal loss in these pathologies.

Introduction

The ability of immunocompetent cells in the peripheral nervous system and central nervous system (CNS) to participate in neurotoxic events implicates these processes in neurological diseases where immune activation has been documented, including Alzheimer's disease (AD), Parkinson's disease (PD), and viral infections. Although distinct in their particular etiologies and susceptible cell types, each disease has pathological components involving immune activation that may directly or indirectly lead to neuronal cell death. Neurotoxic events may be carried out directly by CNS resident immunocompetent cells (microglia and astrocytes), or by infiltrating peripheral monocytes and leukocytes (T-cells and B-cells). Factors produced by these cells may directly contribute to neurotoxicity and include, but are not limited to, antibodies, complement proteins, inflammatory cytokines, chemokines, glutamate, kynurenine metabolites, and reactive oxygen and nitrogen species.

The interplay of the immune system and the central and peripheral nervous systems comprises the basis of the neuroimmune axis concept. Intercellular signaling molecules and proteins of the neuroimmune axis functionally tie the two systems together and regulate the general homeostatic tone of each with the other. When disrupted by external stressors like injury or infection, changes in immune cell activities, which serve to meet both the challenged environment and to provide restorative counterbalancing functions, occur. If unsuccessful, these immune cell changes can lead to chronic inflammation in the brain that disrupts or even damages normal brain function and alter cell viability.

The following five papers in this volume focus on immune system activities thought to be participating in the neurodegenerative processes of AD, PD, and CNS viral infections. The paper by Rampe et al. (2004) investigates the role of microglia in AD inflammation and the potential contribution of ATP to the observed immunopathology. They demonstrate that extracellular ATP stimulation of the purinoreceptor P2X7 has a potential disease-modifying role of shifting the microglial expression of the Aβ-induced cytokines IL-1α, IL-1β, and IL-18 from the cell-associated forms to the secreted forms, thereby perpetuating inflammatory cascades in AD. Li et al. (2004) describe the potential contribution of microglial phagocytosis of DNA fragments from dead cells in the brains of AD individuals to enhanced expression of IL-1β. Their results demonstrate yet another means that inflammatory responses may be perpetuated in AD. The paper by Colton et al. (2004) also addresses AD immunopathology by investigating an often overlooked peripheral immune component of this disease. Specifically, they demonstrate that nitric oxide production from peritoneal macrophages of APOE4 transgenic mice and from blood-derived macrophages of AD patients with the APOE4 genotype is elevated relative to mice and individuals carrying the APOE3 allele. These responses likely reflect an enhanced innate immune response of CNS resident phagocytic cells in APOE4 individuals that contribute to the elevated nitration/nitrosation brain pathology in AD. As a model of PD immunopathology, Wang et al. (2004) describe superoxide anion production by microglia and the resulting neurotoxic effects on dopaminergic neurons in culture. These investigators demonstrate that the neurotoxicity of superoxide anions produced from activated microglia can be attenuated by superoxide dismutase/catalase mimetic compounds, which may be of therapeutic use in treating diseases like PD and AD. Lastly, Njenga et al. (2004) report on T-cell- and B-cell-mediated events accompanying Theiler's virus-induced demyelination and neurotoxicity in the CNS as a model system for leukocyte brain infiltration in viral and multiple sclerosis (MS) immunopathology.