Inflammatory Microglia in Degenerative Aging and Alzheimer's Disease
Microglia, the innate immune cells of the central nervous system, can enter an aggressive, inflammatory state in response to the presence of molecular waste, inflammatory signaling, mitochondrial damage, and so forth. They can also become senescent, which is also a pro-inflammatory state. The aging brain, and particularly the brains of patients with neurodegenerative conditions, exhibit a state of chronic inflammation, producing dysfunction, cell stress, and cell death. It remains to be seen as to how effective anti-inflammatory therapies targeting microglia will be in the treatment of neurodegenerative conditions and the slowing of brain aging. Comparatively simple approaches already exist, such as the use of CSF1R inhibitors to clear existing maladaptive microglia and thereby allow a new population to emerge lacking the damage and inflammatory behavior of the preexisting cells. Time will tell as to their utility.
Current evidence demonstrates that human microglial cells are a hugely varied and heterogeneous population. Microglial heterogeneity is crucial for neurodegeneration, although at the moment it was demonstrated mainly in neurodegenerative mice models. These animal models can only partially clarify what happens in humans due to the fact that Alzheimer's disease (AD) is a proper human disease which is complex and related to both genetic and environmental factors, with a trajectory of evolution that is different and peculiar for each patient. Just think of the association recently demonstrated between imaging markers of microglial reaction and behavioral symptoms in Alzheimer's disease, which is certainly not transferable to mouse models. Thus, the role of microglia in human healthy aging and in AD presents multiple aspects, complex and interconnected.
Although there are huge differences between humans and rodents, mouse models have been very useful to shed light on the microglial role in AD. From our systematic review emerges that microglia have a fundamental role in removing phosphorylated tau protein and harmed synapses and in the phagocytosis and compaction of amyloid-β deposits. All these actions represent the protective aspects of microglia that are crucial to prevent neurodegeneration. This neuroprotective role may become less efficient with advancing age, primarily due to increased oxidative stress and mitochondrial dysfunction. Probably, the loss of efficiency of microglia and the accumulation of protein debris ends up determining a persistent mild inflammation. Therefore, in the brain areas where neurodegenerative phenomena are concentrated, possibly also associated with chronic hypoxia, a pathological context is created in which microglia lose their homeostatic role and become exhausted or dystrophic, otherwise they can become aggressive enhancing neurodegenerative phenomena and synapse loss.
Thus, microglia may contribute to the progression of AD pathology in two ways: through functional exhaustion, with less efficiency in the removal of metabolic waste, or through neurotoxic phenomena due to an excess level of inflammation. Arguably, physiological aging and the maintenance of a healthy brain depends on establishing a balance between the actions and reactions of microglia. These lines of evidence suggest that microglia play a pivotal role in the pathogenesis of AD.