Fight Aging!

Correlations have been found between infectious disease and incidence of neurodegenerative conditions. The dominant hypothesis is that microglia, innate immune cells of the brain, are made more inflammatory by infection, and the resulting chronic inflammation in brain tissue produces dysfunction that contributes to neurodegeneration. The role of microglia in the onset and progression of neurodegenerative conditions is studied more generally as well, as these cells react to signs of damage in aging tissue in much the same way as they react to infection. Further, microglia also enter a state of cellular senescence in increasing numbers with age, becoming highly pro-inflammatory.

A sizable fraction of senescent microglia can be removed by senolytic treatments that pass the blood-brain barrier, such as the dasatinib and quercetin combination, and this has shown benefits in animal models of neurodegeneration. Equally, microglia can be cleared completely from the brain by blocking CSF1R. A new population of microglia is produced and replaces the old within a few weeks, lacking the damage and dysfunction of their predecessors. This too has been shown to produce benefits in animal models of neurodegeneration.

Microglial Priming in Infections and Its Risk to Neurodegenerative Diseases

Infections of different etiologies, neurotropic or not, have been associated with acute and long-term neurological consequences. These consequences involve cognitive decline and behavioral disorders such as depression and anxiety. The main cause of these sequelae is an inflammatory condition in the central nervous system (CNS) characterized by an increase in pro-inflammatory mediators secreted by glial cells, such as microglia and astrocytes.

Microglia, which has long been described as a resident immune cell in the CNS, is currently considered an essential and versatile cell, having well-defined roles in maintaining neuronal networks, supporting synaptic plasticity, repairing injuries, and participating in the inflammatory process. Microglial cells express pattern recognition receptors (PRRs) that recognize molecules known as pathogen-associated molecular pattern (PAMP) molecules and damage-associated molecular patterns (DAMPs). During infection, irrespective of whether the pathogen can invade the CNS, the microglia will respond quickly by altering its state. Once confronted with stimuli, microglia induce and modulate a broad spectrum of molecular and cellular responses in an attempt to eradicate the pathogen.

In recent years, several studies have shown the involvement of the microglial inflammatory response caused by infections in the development of neurodegenerative diseases. This has been associated with a transitory microglial state subsequent to an inflammatory response, known as microglial priming, in which these cells are more responsive to stimuli. Thus, systemic inflammation and infections induce a transitory state in microglia that may lead to changes in their state and function, making priming them for subsequent immune challenges.

Thus, repeated infectious processes can act as a second hit and trigger a response in the primed microglia. However, it is important to emphasize that the aging process itself can be considered a second hit. It was shown that early postnatal infection of rats with LPS combined with the aging process resulted in less successful cognitive aging in these animals. Aging is a risk factor for the development of many neurodegenerative diseases because the natural aging process includes functional and structural changes within the brain. Among these changes is immune system dysfunction, which generates a low-grade chronic pro-inflammatory condition called inflammaging. Considering that microglia are long-lived cells and are repeatedly exposed to infections during a lifetime, microglial priming may not be beneficial, as it may contribute indirectly to neurodegenerative disorders.