Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism

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Abstract

Inflammation, a common denominator among the diverse list of neurodegenerative diseases, has recently been implicated as a critical mechanism responsible for the progressive nature of neurodegeneration. Microglia are the resident innate immune cells in the central nervous system and produce a barrage of factors (IL-1, TNFα, NO, PGE2, superoxide) that are toxic to neurons. Evidence supports that the unregulated activation of microglia in response to environmental toxins, endogenous proteins, and neuronal death results in the production of toxic factors that propagate neuronal injury. In the following review, we discuss the common thread of microglial activation across numerous neurodegenerative diseases, define current perceptions of how microglia are damaging neurons, and explain how the microglial response to neuronal damage results in a self-propelling cycle of neuron death.

Introduction

Inflammation occurs in multiple neurodegenerative diseases, where each disease has unique pathology and symptoms. There is an extensive list of specific triggers of neuronal damage, where each environmental toxin or genetic mutation is specific for a selected disease. However, the gradual accumulation of neuronal death and the increase in disease severity across time is a unifying theme across the diverse classifications of neurodegenerative disease. Previously, inflammation was viewed as only a passive response to neuronal damage. However, increasing reports demonstrate that inflammation is capable of actively causing neuronal death and damage, which then fuels a self-propelling cycle of neuronal death. Thus, while the triggers of various neurodegenerative diseases are diverse, inflammation may be a basic mechanism driving the progressive nature of multiple neurodegenerative diseases. Several cell types have been listed as contributors to inflammation-mediated neurodegeneration, but microglia are implicated as critical components of the immunological insult to neurons. In the following review, we discuss the role of microglia in neuronal death and describe the evidence implicating microglia as a critical mechanism driving the self-propelling nature of neurodegenerative disease.

Section snippets

Glial cells are inflammatory mediators of neurodegenerative disease

Early reports described the brain as an immune privileged organ, due to its compartmentalization and separation from the peripheral blood system, as provided by the blood–brain-barrier. However, most neurodegenerative diseases are characterized by both local inflammation from resident cell types in the brain and by the infiltration of leucocytes from the periphery (Kurkowska-Jastrzebska et al., 1999, McGeer et al., 1989). While infiltrating peripheral immune cells can be significantly toxic to

Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, where neural damage begins in the temporal and parietal lobes of the cerebral cortex and progresses with time to the hippocampus and the amygdala (Braak and Braak, 1994). The result is the loss of language skills, followed by memory decline, and finally delusion in the latter stages. Pathological diagnosis of AD requires identification of insoluble extracellular plaques containing β-amyloid (Aβ) and intraneuronal neurofibrilary tangles

Microglia-mediated dopaminergic neurotoxicity

Dopaminergic neurons are inherently susceptible to the deleterious effects of microglial activation. While the detailed mechanism remains debated, one hypothesis is that the selective mechanism of microglia-mediated dopaminergic neurotoxicity is due to the generation of oxidative insult from microglia. In particular, DA neurons possess reduced antioxidant capacity, as evidenced by low intracellular glutathione, which renders DA neurons more vulnerable to oxidative stress and microglial

Triggers of microglia activation and neurodegeneration

It has become increasingly evident that there are diverse triggers through which microglia are activated to exert their neurotoxicity. Interestingly, while these diverse toxins elucidate several mechanisms of microglial activation, NADPH oxidase activation is also a common pathway through which microglia exert neurotoxicity that is shared across these toxins. These diverse triggers of microglial activation include immunological insult, such as LPS; environmental toxins; endogenous disease

Temporal relationship of the microglial release of neurotoxic factors

The identification of several potential triggers of microglia activation has allowed a generalizable classification of how microglial respond to stimuli. Firstly, based on in vitro culture data, there is a clear temporal relationship between the released microglial neurotoxic factors. Across several toxins, it is apparent that first event is the production of reactive oxygen species (ROS), which includes the extra-cellular superoxide anion (O2radical dot−) and an increase in iROS (Gao et al., 2002b, Qin

Microglial activation as a common mechanism in diverse neuropathology

While we have highlighted the common mechanisms of how microglia respond to various toxins and signals to result in selective DA neuron toxicity, we have also presented evidence indicating that microglial activation contributes to unique pathology associated with multiple neurodegenerative diseases. The intriguing question remains as to how the generalized phenomena of microglial activation can result in diverse and localized neurodegenerative pathology. While this is a complex issue that is

Conclusions

Microglia are the critical actors of self-propelling mechanisms of neurotoxicity (reactive microgliosis), which is an underlying contributing mechanism to multiple neurodegenerative disorders. Microglia can be activated by two mechanisms: (1) direct stimulation of microglia from environmental or endogenous toxins; (2) activation through a reactive microgliosis process. Oxidative stress is predominant in neurodegenerative disease and microglia are critical sources of oxidative insult. In

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