Microglia and neuroprotection: implications for Alzheimer's disease

Abstract

The first part of this paper summarizes some of the key observations from experimental work in animals that support a role of microglia as neuroprotective cells after acute neuronal injury. These studies point towards an important role of neuronal–microglial crosstalk in the facilitation of neuroprotection. Conceptually, injured neurons are thought to generate rescue signals that trigger microglial activation and, in turn, activated microglia produce trophic or other factors that help damaged neurons recover from injury. Against this background, the second part of this paper summarizes recent work from postmortem studies conducted in humans that have revealed the occurrence of senescent, or dystrophic, microglial cells in the aged and Alzheimer's disease brain. These findings suggest that microglial cells become increasingly dysfunctional with advancing age and that a loss of microglial cell function may involve a loss of neuroprotective properties that could contribute to the development of aging-related neurodegeneration.

Introduction

One of the most basic tenets of neurobiology is that glial cells function to provide metabolic, structural, and trophic support to neurons. Glia are essential supporting cells and without them nervous tissue would not be viable. Classic examples of glial cell support include myelination of axons by oligodendrocytes to facilitate nerve impulse conduction and glutamate uptake by astrocytes to protect neurons from excitotoxicity. In the case of microglia, their normal physiological functions are not as well understood but there is good reason to believe that microglia provide neuroprotection in a variety of ways. Research in recent years has helped consolidate the view of microglia as the brain's endogenous immune system and thus microglia should be seen as the first line of defense in acute “emergency” situations, such as physical/chemical or hypoxic injury or infectious diseases. However, when it comes to chronic neurological diseases, particularly neurodegenerative conditions, such as Alzheimer's disease (AD), the role of microglia is not entirely clear. Over the last fifteen years, many researchers have pursued the idea that neurodegeneration in AD is mediated in part by a chronic neuroinflammatory response of microglial cells to amyloid-β (Aβ) protein, and this has led to clinical trails with nonsteroidal anti-inflammatory drugs (NSAIDs). Results from these trials remain equivocal thus far. More recently, attention has shifted towards a completely different, potential therapeutic strategy, namely, immune stimulation, the idea being that vaccination with Aβ peptides will cause microglia to more efficiently phagocytose amyloid deposits removing what it is thought by many to be the direct cause of neurodegeneration. This approach has encountered problems of its own that are beyond the scope of this paper and discussed elsewhere [18], [20]. The current paper is focused on another possibility that is just beginning to emerge and this concerns the loss or the deterioration of normal physiological microglial cell function [28], [29]. There are now data showing that microglial cells are subject to age-related structural deterioration and cellular senescence [7], [37]. It also appears that microglial cellular senescence is exacerbated in the presence of Aβ suggesting that Aβ may adversely affect physiological functions of microglia by hastening the cells' structural decline [11]. Thus, as microglial cell function deteriorates with aging, there may be an increasing disability of microglia to provide neuroprotection. This waning glial support could contribute to age-related neurodegenerative disease. At the same time, if microglial ability to clear away Aβ was also impaired by cell senescence, it would explain why Aβ accumulates extracellularly and forms amyloid plaques. This paper summarizes some of the experimental results and reasoning that have led to postulating a microglial dysfunction hypothesis as a possible pathway in AD pathogenesis [30].