Trends in Neurosciences
OpinionMicroglial senescence: does the brain's immune system have an expiration date?
Introduction
Acute injury to the CNS triggers a rapid cellular response that is spearheaded by microglia as the principal element of neuroinflammation. Injury-induced activation of microglia is evident in situ as the morphological transition of resting microglia into activated or reactive microglia [1]. Along with cellular hypertrophy and an increase in cell number, microglial activation also entails a multitude of biochemical and metabolic changes that increase the ability of cells to cope with the drastic changes in tissue homeostasis that occur inevitably as a consequence of injury. With reference to a recent TINS article by Raivich [2], if one were to extend the analogy that resting microglia are like cops on the beat, one could liken activated microglia to the police department Special Weapons and Tactics (SWAT) team, a special force trained to perform dangerous operations. Microglial activation involves increased recruitment of cells, primarily through mitosis of resident microglia but also from bone-marrow-derived precursors that infiltrate the CNS. The ability of microglia to divide distinguishes them from most other CNS cell types, and it raises questions about their lifespan and self-renewal capacity. How long do microglia live? How many cycles of cell division can occur before the cells experience critical telomere shortening and enter replicative senescence? How is the self-renewal potential of microglia affected by aging? Do factors other than old age adversely affect microglial self-renewal, vitality and function? And if so, what are they? To date these questions remain largely unanswered, but different lines of emerging evidence from humans and rodents suggest that senescence of microglia does occur. If microglia indeed have an expiration date, one is tempted to speculate on the consequences for neurons. Here, I propose that severe deterioration of microglial viability and/or function can lead to neurodegeneration.
Section snippets
Neuroinflammation – why it's a good thing
To make the argument that microglia are crucial in neuronal survival it seems fitting to begin with a classic example of a localized microglial neuroinflammatory reaction – facial nerve axotomy (Figure 1). Detailed descriptions of this well-studied experimental paradigm can be found elsewhere 3, 4, 5, suffice to say here that the microglial reaction is initiated before and persists during the period when motoneurons regenerate their axons and eventually regain function. Axonal regeneration is
Replenishment and death of microglia
As endogenous immune defenders of the CNS, microglia must be resistant to potentially damaging influences such as radiation, free radicals, toxins or drugs. That microglia can divide contributes significantly to their resilience by making possible their self-renewal. Mitotic capacity also implies that the lifespan of an individual microglial cell is limited, but regrettably the specific number of cell divisions that are possible before death is not known. It is known that microglia undergo a
Effects of aging on microglial mitosis and replicative senescence
Insights regarding the dynamics of microglial proliferation have been gained almost exclusively through DNA-labeling studies in rodents during experimental brain injuries. The robust mitotic potential of microglia during activation is undiminished by old age – in fact, microglia appear to proliferate even more vigorously in older rats after a facial nerve lesion [26]. Although this ability to respond to injury is clearly different from replicative senescence, which refers to the eventual loss
Structural deterioration of microglia might contribute to aging-related neurodegeneration
Although rodent microglia undergo phenotypical and morphological changes with normal aging 26, 29, they display relatively homogeneous morphology with little variation among individual cells. By contrast, human microglia can demonstrate extraordinary heterogeneity in their cytoplasmic structure, even in subjects who have no evidence of neurological disease (Figure 2). Recent work from my laboratory has resulted in the identification of so-called dystrophic microglia in the human brain [30].
Concluding remarks
The accumulation of dystrophic microglia in the aging human brain strongly suggests that this cell population is undergoing progressive deterioration. The wear and tear on microglia probably results from a combination of diminished replenishment and increased cell vulnerability due to various factors that might include presence of β-amyloid protein. Based on the notion that microglia are inherently beneficial for maintaining normal brain function, deterioration of this cell population could be
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