Neuroinflammation and its Role in the Pathophysiology of Alzheimer\'s disease

Torkmahalleh Feinberg

Introduction

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, affecting millions of individuals worldwide. As the global population ages, the prevalence of AD is expected to rise, making it a critical area of research for understanding and managing cognitive decline. Although significant advances have been made in identifying the hallmark features of AD, such as amyloid plaques and tau tangles, the underlying mechanisms of disease progression remain poorly understood. In recent years, increasing attention has been directed toward the role of neuroinflammation in the pathophysiology of Alzheimer's disease [1].

Neuroinflammation refers to the inflammatory response within the brain, which involves the activation of glial cells-microglia, astrocytes and oligodendrocytes-in response to various pathological stimuli. The activation of these cells is thought to play a crucial role in both the initiation and progression of AD. This article explores the current understanding of neuroinflammation in Alzheimer's disease, examining its molecular pathways, the interaction between inflammation and other pathological features and its potential implications for therapeutic strategies [2].

Description

The brain is a highly sensitive organ, capable of responding to various forms of injury, infection, or dysfunction through an inflammatory response. In the context of Alzheimer's disease, neuroinflammation is generally triggered by the accumulation of amyloid-β (Aβ) plaques, tau tangles, oxidative stress and neuronal injury. These stimuli activate the brain's immune system, which is primarily composed of glial cells. These cells, particularly microglia and astrocytes, play vital roles in maintaining brain homeostasis and protecting against neuronal damage. Microglia are the resident immune cells of the Central Nervous System (CNS), acting as the brain’s primary defenders against damage and infection. Under normal conditions, microglia survey the brain for signs of injury or infection. In Alzheimer's disease, however, the chronic accumulation of Aβ plaques can cause microglia to become hyperactivated. This prolonged activation is associated with the release of pro-inflammatory cytokines and other mediators that can exacerbate neuronal damage. While microglial activation initially serves a protective function, over time, it can contribute to neurodegeneration and the progression of Alzheimer's disease [3].

Astrocytes are another key type of glial cell involved in neuroinflammation. They provide metabolic support to neurons, regulate blood-brain barrier integrity and modulate synaptic function. In AD, astrocytes become reactive and release inflammatory molecules, such as cytokines and chemokines. This reactive state is linked to synaptic dysfunction and the disruption of normal neuronal signaling, further contributing to the cognitive decline observed in Alzheimer's disease. Though less studied than microglia and astrocytes in the context of AD, oligodendrocytes play a role in myelin maintenance and repair. In neuroinflammation, oligodendrocytes are often damaged, leading to myelin loss, which disrupts axonal communication. This myelin loss is thought to contribute to the cognitive deficits observed in Alzheimer's patients. The accumulation of amyloid-β (Aβ) plaques in the brain is one of the defining features of Alzheimer's disease. Aβ is a peptide that forms sticky aggregates, which are toxic to neurons and trigger inflammation. When Aβ plaques accumulate, they activate microglia, which attempt to clear the plaques but are often overwhelmed by the load. The microglia then release a variety of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and Reactive Oxygen Species (ROS), which can exacerbate neuronal injury and further activate surrounding glial cells [4].

Chronic neuroinflammation is detrimental to brain health and contributes significantly to the progression of Alzheimer's disease. While acute inflammation is a protective response aimed at clearing damage or infection, chronic inflammation leads to a sustained release of inflammatory mediators that can damage neurons, impair synaptic plasticity and disrupt brain function. One of the key mechanisms through which neuroinflammation contributes to neuronal damage is the activation of inflammatory cytokines, which alter synaptic function and promote neuronal apoptosis. For instance, TNF-α and IL-1β are known to impair synaptic transmission and plasticity, key processes involved in learning and memory. Additionally, the continuous production of reactive oxygen and nitrogen species (ROS and RNS) can cause oxidative damage to lipids, proteins and DNA, further exacerbating neuronal dysfunction and death. The Blood-Brain Barrier (BBB) also plays a crucial role in maintaining the brain's immune privilege. However, during chronic inflammation in Alzheimer's disease, the BBB becomes more permeable, allowing peripheral immune cells, such as T cells and monocytes, to infiltrate the brain. This recruitment of peripheral immune cells exacerbates neuroinflammation, creating a feedback loop that accelerates the progression of the disease [5].

Conclusion

Neuroinflammation plays a central role in the pathophysiology of Alzheimer's disease, contributing to the initiation and progression of the disorder. The activation of glial cells, particularly microglia and astrocytes, in response to amyloid-β plaques, tau tangles and oxidative stress creates a chronic inflammatory environment that exacerbates neuronal damage. The interactions between neuroinflammation and other pathological features of AD, such as amyloid plaques and tau, create a vicious cycle that accelerates disease progression. While there is still much to learn about the precise mechanisms underlying neuroinflammation in Alzheimer's disease, the growing body of evidence highlights the potential for targeting neuroinflammatory pathways as a therapeutic strategy. Modulating the immune response in the brain offers hope for slowing or halting the progression of Alzheimer's disease and improving the quality of life for patients. Further research is needed to better understand the complexities of neuroinflammation and to develop safe and effective treatments for this devastating condition.

Acknowledgement

None.

Conflict of Interest

None.

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