The neurons of the brain form intricate, shifting networks of synaptic connections. Synapses are constantly created and destroyed in regions important to memory and learning, and supporting cell populations of the brain aid in this process. Microglia, for example, are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Ingesting and destroying unwanted synapses is one of the tasks undertaken by this cell population. In recent years, researchers have focused on dysfunction in microglia as an important contribution to pathology in inflammatory neurodegenerative conditions. Microglia become more inflammatory, change their behavior in other ways, and a fraction of these cells become senescent. Senescent cells cease to replicate, further alter their behavior, and generate a potent mix of pro-inflammatory and pro-growth signaling.
In today's open access paper, researchers investigate how senescent microglia might contribute to the known pathologies observed in inflammatory neurodegenerative conditions. The scientists demonstrate in mice that the presence of senescent microglia causes an increased pace of destruction of synapses. Some destruction is necessary to adjust neural networks, but too much destruction causes cognitive dysfunction, an outcome characteristic of brain inflammation. It is possible to clear microglia generally, using CSF1R inhibitors, or selectively destroy only senescent cells in the brain using some of the first generation senolytics - the dasatinib and quercetin combination passes the blood-brain barrier. This approach to treatment will likely be beneficial, but progress towards clinical use in this context is slow.
Microglia-mediated neuroinflammation has been shown to exert an important effect on the progression of a growing number of neurodegenerative disorders. Prolonged exposure to detrimental stimuli leads to a state of progressive activation and aging-related features in microglia (also termed as senescent microglia). However, the mechanisms by which senescent microglia contribute to neuroinflammation-induced cognitive dysfunction remain to be elucidated.
Here, we developed a mouse model of neuroinflammation induced by lipopolysaccharides at 0.5 mg/kg for 7 consecutive days. To evaluate cognitive function, C57BL/6J mice were employed and subjected to a series of behavioral assessments, including the open field, Y-maze, and novel object recognition tests. Employing single-cell RNA sequencing technology, we have delved into the differential expressions of RNA within microglia. Furthermore, to investigate anatomic and physiological alterations of pyramidal neurons, we utilized Golgi staining and whole-cell patch-clamp recordings, respectively. Validation of our results in protein expression was performed using western blotting and immunofluorescence.
We specifically identified senescent microglia with a high expression of p16INK4a and observed that microglia in the hippocampal CA1 region of the model exhibited signatures of elevated phagocytosis and senescence. A senolytic by ABT-737 treatment alleviated the production of senescence-associated secretory phenotypes, the accumulation of senescent microglia, and the microglial hyperphagocytosis of excitatory synapses following LPS exposures. This treatment also restored reduced excitatory synaptic transmission, impaired long-term potentiation, and cognitive function in the model. These results indicate that reducing senescent microglia may potentially serve as a therapeutic approach to prevent neuroinflammation-related cognitive dysfunction.
View the full article at FightAging
