The progressive age-related dysfunction of microglia in the aging brain is implicated in the progression of neurodegenerative disease, as well as the increased inflammation and forms of pathology found in the brain tissue of older individuals. In mice, clearance of microglia can be efficiently achieved and leads to a rapid repopulation of the brain with new microglia, as well as improvements in measures of brain function. Similarly, targeted destruction of senescent microglia and other supporting cells in the brain via the use of senolytic drugs that can pass the blood-brain barrier has been shown to reduce chronic inflammation and pathology in mouse models of neurodegeneration.
Microglia, far from being simply 'brain glue', play an important role as the brain's resident immune cells. There is some precedent for the toxicity of senescent cells, with several studies identifying that the elimination of senescent cells as potential mechanisms for countering their deleterious effects. In the case of microglia, senescence as a descriptor is sometimes used interchangeably with dystrophic. 'Dystrophy' now tends to refer more to morphological changes, whereas 'senescence' may be used to refer to specific secretory phenotypes, particularly associated with ageing. These features have been observed in healthy but aged brains, although it has also been suggested by a study using human brain tissue that senescent microglia are exclusively a disease-associated phenotype.
Specific depletion of microglia by targeting of Colony Stimulating Factor 1 Receptor (CSF1R) has been utilised in mouse models, for the purpose of impeding the propagation of phospho-tau, such as is observed in Alzheimer's disease. However, even as this demonstrates the principle of specifically targeting microglia, such a large scale depletion of the cell type is likely to be of limited practical benefit in a clinical setting. CSF1R inhibition in mouse models has been shown to eliminate 99% of CNS microglia. Inhibition of CSF1R, then removal of this inhibition for 1 week, was demonstrated to allow 'repopulation' of microglia, while triggering no cognitive, motor function, or behavioural deficits.
It remains to be seen if this approach would be so successful in the larger, more complex human brain, where cell volume is substantially greater than in the mouse. Microglial elimination and repopulation in an aged mouse model was shown to improve cognition, particularly spatial memory, concurrently increasing density of synaptic spines and neurogenesis. These processes are diminished in the aged brain, demonstrating benefit not only to the microglia but also to the surrounding neurons.
Targeting and eliminating or reprogramming aged or senescent microglia clearly holds potential for reversing the impact of ageing on the brain, and much has already been learned from such techniques. However, at the present time, it remains unclear how these techniques might be translated into benefit in human patients. An ideal outcome would be the ability to target specifically aged, senescent, and neurotoxic microglia and eliminate them from the brain without the requirement for genetic manipulation and transgene expression. Efficacy of such a technique may well be improved by more specific identification and targeting of senescent microglia, which would require the identification of a unique, specific marker.