Journal of Alzheimers Disease & Parkinsonism
Open Access

Microglial activation refers to the process by which microglia, the resident immune cells of the Central Nervous System (CNS), respond to injury, infection, or disease by changing from their resting surveillance state into an active state. Microglia play a critical role in maintaining brain homeostasis, monitoring the environment for signs of trouble, and defending against pathogens or clearing damaged cells. When activated, microglia undergo morphological and functional changes, including enlargement of their cell bodies, retraction of their branching processes, and upregulation of surface receptors. They also release a variety of signaling molecules such as cytokines, chemokines, reactive oxygen species, and growth factors, which collectively orchestrate the immune response within the brain.

Microglial activation is a necessary and beneficial process in acute situations like infection, trauma, or ischemia, where it helps clear pathogens, remove cellular debris, and promote tissue repair. However, when activation becomes chronic or excessive, it can contribute to neuroinflammation and neurodegeneration. Sustained microglial activation has been implicated in many neurological diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. In these conditions, microglia may adopt a pro-inflammatory phenotype, releasing molecules that damage neurons and exacerbate disease progression rather than supporting repair.

The triggers for microglial activation are diverse. They include the presence of pathogens, damaged neurons, protein aggregates such as amyloid-beta or alpha-synuclein, and signals from other glial cells or infiltrating immune cells. Microglia express a variety of receptors, including Toll Like Receptors (TLRs), purinergic receptors, and cytokine receptors, which detect these danger signals and initiate the activation process. Once activated, microglia can adopt different functional states, often categorized broadly as pro-inflammatory or anti-inflammatory/ reparative though in reality, their phenotypes exist on a spectrum and can shift dynamically depending on the microenvironment.

In the pro-inflammatory state, microglia produce cytokines such as tumor necrosis factor-alpha interleukin-1 beta and interleukin-6 along with reactive oxygen and nitrogen species. These molecules can lead to oxidative stress, synaptic dysfunction, and neuronal injury. Conversely, in their anti-inflammatory or reparative state, microglia release factors that promote tissue repair, phagocytose debris, and support neuron survival. The balance between these states is critical for brain health.

Microglial activation is tightly regulated through complex signaling pathways and interactions with other CNS cells, including neurons and astrocytes. Neurons can produce off signals such as fractalkine (CX3CL1) and CD200 that keep microglia in a resting state under normal conditions. Disruption of these regulatory signals can contribute to unchecked microglial activation and inflammation. The study of microglial activation has advanced significantly with new tools like in vivo imaging, transcriptomic analysis, and the development of specific markers.

Microglial activation is a fundamental immune response within the CNS that plays a dual role: protecting the brain from damage but also contributing to pathology when dysregulated. Understanding the complex biology of microglial activation is key to developing therapies that can harness their protective functions while minimizing their harmful effects in neurological disorders. These advances help differentiate between beneficial and harmful microglial responses and identify therapeutic targets. Modulating microglial activation is a promising avenue for treating neurodegenerative diseases and brain injuries. For example, drugs that shift microglia from a proinflammatory to a reparative state, or that inhibit excessive activation, are being explored in preclinical and clinical trials.