Astrocyte and Microglial Contributions to Neurodegeneration in the Aging Brain

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Introduction

Aging is a biological process that occurs at every cellular, tissue, and organic level in living organisms, including the human brain. One of the more devastating effects of aging is the susceptibility of the CNS not only to such diseases as Alzheimer’s, Parkinson’s, and other forms of dementia but also to any pathology in which CNS injury may prove lethal. Two important actors in the aging brain are astrocytes and microglia, which are glial cells, and although they are not neurons, they play a vital role in the health of the brain and the nervous system in general. Though these changes occur during the deterioration of neurogenic potential with the aging of the brain, astrocytes and microglia contribute to neurodegeneration. In this article, the author looked at how astrocytes and microglia, which are referred to as the brain’s “glue cells,” change with age and how this triggers neurodegenerative diseases.

Astrocytes: Guardians Turned Contributors to Neurodegeneration

Astrocytes are the most numerous glial cells in the CNS; they are involved in the support of neurons, regulation of blood flow, and formation of the blood-brain barrier. In their positions, astrocytes have been known to contribute to the removal of neurotransmitters from the synaptic cleft, supply nutrients to neurons, and regulate synapse transmission. Nevertheless, normal astrocytes in the aging brain look different morphologically, functionally, and physiologically from the youthful ones; these changes show that the astrocytes function abnormally.

A noteworthy feature among the ultrastructural modifications observed within aged astrocytes is a failure to regulate intracellular ion homeostasis. Astrocytes in the aging brain are characterized by an enlargement of the cell soma and the thinning and retraction of processes, which can limit the cells’ ability to communicate with neurons or other astrocytes. This hypertrophy is coupled with up-regulation of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytes. Reactive astrocytes are capable of releasing inflammatory cytokines and chemokines, which increase neuroinflammation and help in the progression of neurodegenerative disorders.

This finding can be further supported by the ability of astrocytes to control the cerebral oxidative stress in the CNS. Astrocytes have antioxidant capabilities within the brain, and it has been established that when these cells age, they are unable to provide the normal levels of antioxidant protection they used to; therefore, they allow increased levels of oxidative stress, which is pro-neuronal damage. An increase in ROS production and the ability of astrocytes to scavenge these toxic molecules may enhance neuronal death and worsen neurodegeneration. Furthermore, reactive astrocytes display a defective function of glutamate uptake, which gives rise to excitotoxicity or the neuropathological frustration that results from excessive accumulation of glutamate that is toxic to neurons.

Astrocytes also ch­ange the ways they interact with other glial cells, particularly microglia. With age, changes in the crosstalk between astrocytes and microglia may destabilize the homeostasis needed for physiological CNS function. For example, astrocytes can secrete factors that can promote microglial activation or have an inhibitory effect, thus acting as moderators of inflammation in the brain. Dysfunctional communication of this nature is seen as a substantial element of the neurodegenerative cascade seen in aging.

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Microglia: The Double-Edged Sword of Neuroinflammation

Microglia are the specialized immune cells of the CNS that remain active throughout the life of an individual and are tasked with the responsibility of constantly scanning the brain microenvironment for any signals of invader pathogens, injury, or pathological cellular activation. Under normal circumstances, microglia are the beneficial cells in the healthy young brain; they ‘scavenge’ the environment by removing unwanted pieces, engulfing and digesting cells that have died naturally, known as apoptosis, and releasing chemical signals that promote neuronal survival. However, in the aging brain, the resting state microglia are in a ‘primed’ state where they have become hypersensitive to inflammatory signals and respond aggressively to any provocation.

Whereas young microglia have many thin processes and small soma, the aged microglia are more rounded and have a large soma with few branches. This altered morphology correlates with functional changes in which the microglia lose their ability to effectively eliminate debris and increase the production of pathogenic cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and other inflammatory molecules that fuel chronic neuroinflammation. Such a chronic inflammation condition is referred to as “inflammaging” and is widely known to precipitate neurodegeneration.

Microglial movement and positioning help them to take up dying cells and abnormal protein aggregation, which is one of their main responsibilities. In the aging brain, thereby proboscis, microglial phagocytic function becomes dysregulated and exacerbates amyloid-β plaques in Alzheimer’s disease and other neurodegenerative diseases. Also, it was revealed that in microglia found in the brains of aged animals, neuropathy may start; this is when microglia start to engulf healthy neurons and synaptic elements. This additional aberrant activity can exacerbate the conditions of neuronal networks and also hasten cognition.

Furthermore, microglial crosstalk with astrocytes is also altered with the advancement in age. These findings illustrated that microglia can directly activate astrocytes to their reactive form and thus create a cycle of neuroinflammation. Conversely, activated reactive astrocytes can secrete factors that further activate microglia and form a cycle of continual inflammation and tissue pathology. Their reciprocal interaction plays a critical role in neurodegenerative disease processes, implying that therapies targeting astrocytes and microglial cells simultaneously should be effective.

Astrocyte-Microglial Crosstalk: A Complicated Relationship

Astrocytes and microglia are in crosstalk with each other, meaning that when one of the two cell types releases some signal, the second type of cell will act in response to it. Consumption of A3 rice helped modulate the pathophysiology of both astrocytes and microglia in the aging brain and the resulting neurodegeneration. For instance, the microglia discharge the pro-inflammatory proteins in the form of extracellular vesicles, and these vesicles can be internalized by the astrocytes, thus increasing their reactive state. On the other hand, productive forms of astrocytes can also secrete cytokines such as IL-33 that activate microglia and modulate inflammation.

Astrocytes and microglia also interface with the extracellular matrix (ECM), and modification of the ECM in the aged brain impacts glial function. Accumulation of some de novo synthesized abnormal ECM proteins has been related to increased activation of astrocytes and microglia, leading to sustained inflammation in the aging process. These interactions with the ECM add additional layers to the regulatory roles that these glial cells exhibit in the aging brain and shift the balance from protection towards neurodegeneration.

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Implications for Therapeutic Interventions

Despite some limitations, this contribution reveals the critical functions of astrocytes and microglia in the aging brain and offers a new perspective on therapeutic approaches to neurodegenerative diseases. The modulation of reactive glial cells and the use of therapies that target inflammation may offer neuroprotection for neurons that remain affected by inflammation. These could include coding or changing signal intensity that triggers astrocyte and microglial activation, promoting their beneficial functions, or reintroducing their CNS reparative role.

Examples include preventing the activation of microglia or increasing their efficiency in clearing toxic proteins such as those found in Alzheimer’s disease. Likewise, stimulating antioxidant activity in astrocytes could reduce oxidative stress, making neurons safe from excitotoxicity and other ailments.

Also, treatments aimed at modulating astrocyte and microglia aberrant communication may be most helpful. From there, it may become possible to intervene with the signaling molecules that regulate the interaction between astrocytes and microglia that sustain the feedback loops between neuroinflammation and neurodegeneration in the aging brain.

Conclusion

The human brain, in the absence of optimal functioning, marks the start of aging; astrocytes and microglia initially regarded as simple supporters of neurons assume critical roles in the advancement of neurodegenerative diseases. It was outlined that the protective glial cells turned into toxic pro-oxidant inducers of neurodegeneration and therefore imply the necessity of targeting glial cell dysfunction in therapeutic strategies involved in age-related neurological diseases. Based on research on astrocytes and microglia, it is quite possible to find amicable ways of tackling neurological disorders in the elderly and eliminating the impacts of these diseases.

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