Recent Reviews Covering the Role of Glial Cells in Aging
Glial cells perform many vital tasks in the brain and other nervous system tissues, and age-related changes in their behavior are a part of the progression of neurodegenerative conditions. In the last couple of months a fair number of very readable review papers on this topic have been published. If you are interested in learning more about this aspect of the brain, now is your chance; take a look at the reviews referenced below.
There are many varied types of glia, each with a different role. Some provide structure and nutrients so as to support neurons, others appear essential to activities such as the formation of synaptic connections, or undertake immune system functions such as the destruction of invading pathogens. Much of the focus in the study of glia falls upon microglia, which carry out immune functions, and astrocytes, which have a very broad portfolio of responsibilities and contributions: near every aspect of the brain's operation is influenced by or dependent upon their activities. In the study of the aging brain, rising levels of chronic inflammation and dysfunction of specific mechanisms are both topics of interest. Microglia mediate inflammation, while many neural mechanisms disrupted in the progression of neurodegenerative disorders involve astrocytes in one way or another.
Neuroinflammation: good, bad, or indifferent?
Under non-diseased conditions, central nervous system (CNS) homeostasis is maintained by an intricate crosstalk between glia and neurons. For example, astrocytes play a key role in neurogenesis, metabolism, and regulating neuronal activity at the tripartite synapse. Microglia are continuously surveying their microenvironments for foreign antigens and are important phagocytes, playing roles in synaptic pruning and clearance of apoptotic debris. However, in response to CNS infection or injury, these glial cells become activated and contribute to ensuing inflammatory processes, in either a beneficial or detrimental manner, depending on the nature, intensity, and duration of the insult. Yet, another wrinkle to this paradigm is the fact that many immune-related molecules can possess secondary functions in the CNS, which expands their portfolio of action.
It is now evident that many diseases affecting the CNS have some inflammatory component, either as a primary cause or secondary outcome of tissue damage. Much work remains to be done to identify the critical mediators and cell types involved; however, this will prove to be a challenging task given the complexities already uncovered with regard to the timing, context, and crosstalk between individual inflammatory molecules. Nonetheless, harnessing inflammation to promote CNS healing/regeneration remains an area of active investigation.
New advances on glial activation in health and disease
In addition to being the support cells of the central nervous system (CNS), astrocytes are now recognized as active players in the regulation of synaptic function, neural repair, and CNS immunity. Astrocytes are among the most structurally complex cells in the brain, and activation of these cells has been shown in a wide spectrum of CNS injuries and diseases. Over the past decade, research has begun to elucidate the role of astrocyte activation and changes in astrocyte morphology in the progression of neural pathologies, which has led to glial-specific interventions for drug development. Future therapies for CNS infection, injury, and neurodegenerative disease are now aimed at targeting astrocyte responses to such insults.
Impact of age-related neuroglial cell responses on hippocampal deterioration
Aging is one of the greatest risk factors for the development of sporadic age-related neurodegenerative diseases and neuroinflammation is a common feature of this disease phenotype. In the immunoprivileged brain, neuroglial cells, which mediate neuroinflammatory responses, are influenced by the physiological factors in the microenvironment of the central nervous system (CNS). These physiological factors include but are not limited to cell-to-cell communication involving cell adhesion molecules, neuronal electrical activity and neurotransmitter and neuromodulator action. However, despite this dynamic control of neuroglial activity, in the healthy aged brain there is an alteration in the underlying neuroinflammatory response notably seen in the hippocampus, typified by astrocyte/microglia activation and increased pro-inflammatory cytokine production and signaling. These changes may occur without any overt concurrent pathology, however, they typically correlate with deteriorations in hippocamapal or cognitive function.
Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis
Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.
Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity?
An emerging aspect of neuronal-glial interactions is the connection glial cells have to synapses. Mounting research now suggests a far more intimate relationship than previously recognized. Moreover, the current evidence implicating synapse loss in neurodegenerative disease is overwhelming, but the role of glia in the process of synaptic degeneration has only recently been considered in earnest. Each main class of glial cell, including astrocytes, oligodendrocytes, and microglia, performs crucial and multifaceted roles in the maintenance of synaptic function and excitability. As such, aging and/or neuronal stress from disease-related misfolded proteins may involve disruption of multiple non-cell-autonomous synaptic support systems that are mediated by neighboring glia. In addition, glial cell activation induced by injury, ischemia, or neurodegeneration is thought to greatly alter the behavior of glial cells toward neuronal synapses, suggesting that neuroinflammation potentially contributes to synapse loss primarily mediated by altered glial functions.
Astrocytes in physiological aging and Alzheimer's disease
Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contributes to the aging of the brain and to neurodegenerative diseases. Changes in astroglia in aging and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter the homeostatic reserve of the brain and contribute to early cognitive deficits. At later stages of AD reactive astrocytes are associated with neurite plaques, the feature commonly found in animal models and in human diseased tissue. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at the prevention and cure of neurodegenerative disorders.
Microglia as a critical player in both developmental and late-life CNS pathologies
Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies.