Chronic Neurovascular Inflammation in the Aging Brain

The evidence strongly suggests that chronic inflammation in brain tissue is of great importance in the onset and progression of age-related neurodegenerative conditions. Overactivation of the immune system, resulting in chronic inflammation, is a feature of aging. It arises in part due to the accumulation of senescent cells and their inflammatory secretions, but persistent viral infection and a range of other mechanisms are also implicated.

Inflammaging represents a persistent low-grade systemic inflammation with inapparent clinical symptoms. In fact, it operates as a seesaw with a progressive pro-inflammatory "overload". Cytokines, such as interleukins and tumor necrosis factor α (TNFα), as well as a gamut of self-debris originated from dysfunctional cells fuel the constant activated state of the immune system. With aging, accumulation of these endogenous signals is less compensated by the autophagic machinery. These stressors function as damage-associated molecular patterns (DAMPs), activating the pattern recognition receptors (PRRs) of the innate immune system.

In the brain, the neurovascular unit (NVU) establishes an intimate structural and functional connection among microvascular endothelial cells, pericytes, glial cells, neurons, and extracellular matrix components. Primary functions of the NVU are the development and maintenance of the blood-brain barrier (BBB) and neurovascular coupling. Cells of the NVU are also recognized for the role in the regulation of inflammation in the central nervous system (CNS). Inflammasome receptors appear to have a defined expression in cell types of the NVU with predominant expression of NLRP3 in endothelial cells. Experimental data strongly indicate that brain vasculature is as much affected by inflammation as neural tissue. A growing body of literature supports the idea that the NVU takes center stage in age-related neurological diseases, and of this, inflammasomes are undoubtedly crucial mediators.


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