Astrocyte and Microglial Contributions to Neurodegeneration in the Aging Brain

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.

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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