Chronic inflammation in brain tissue is thought to be important in the progression of neurodegenerative conditions such as Alzheimer's disease. Some factions within the research community theorize that chronic inflammation driven by dysfunctional microglia and other supporting cells in the brain is the important cause of Alzheimer's, not the early accumulation of amyloid-β. Even as it becomes inflammatory with advancing age, the immune system continues to perform necessary functions, however. So any approach to addressing the issue must be fairly selective. An example is the use of senolytic drugs capable of passing the blood-brain barrier in order to destroy senescent microglia and astrocytes, a strategy that, in mouse models, has been shown to reverse the tau pathology characteristic of the later stages of Alzheimer's disease.
While there is consensus that the immune system is intimately involved in Alzheimer's disease (AD), there is considerable debate over which aspects of inflammation are harmful and contribute to degeneration, and which are protective and may prevent cognitive decline. Furthermore, it has yet to be established which components of the immune system actively play a role in pathology and which are just a consequence of disease. Gliosis, or increased numbers of activated astrocytes and microglia are a hallmark feature of neuroinflammation. However, past descriptions of this phenomenon, namely just "reactive" or "increased gliosis" are vastly oversimplified. Recent evidence highlights altered glia-specific pathways in post-mortem AD tissue and in mouse models of AD, suggesting that glial responses are much more heterogeneous and complex than previously thought.
While neuroinflammation can promote efficient clearance of amyloid-β and neuronal debris it can also accelerate disease by causing neuronal and glial cell death. This inflammatory balance is highly orchestrated and understanding how to regulate these responses is key to developing effective therapeutics for AD. The initiation of an immunological reaction can be beneficial and critical, allowing for a burst of glial activity to protect and repair the site of damage, and to clear toxic species or dysfunctional synapses. For example, in response to adverse conditions, microglia will undergo morphological changes, accompanied by the release of a storm of molecular mediators that increases clearances of amyloid-β. Furthermore, various types of non-neuronal cells are recruited to the site to assist in repairing the damage and consolidating excessive inflammation. These reparative processes are beneficial, yet may also have harmful consequences such as sustained cytokine release which can become toxic to neuronal cells. Therefore, understanding the specific cellular roles and inflammatory reactions in AD is of vital importance.
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