Towards Depletion of Microglia as a Treatment for Alzheimer's Disease
In recent years, increasing attention has been given to the role of microglia in neurodegenerative conditions. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body, but which also participate in the organization of synaptic connections in addition to the other roles one might expect from immune cells. Microglia in the aging brain become more inflammatory and overactive with age. Some become senescent. This contributes to the chronic inflammation of brain tissue observed in older individuals, and which contributes to the onset and progression of neurodegenerative conditions. Interestingly, it is possible to efficiently clear microglia using CSF1R inhibitor drugs, after which the population is recreated over the course of a few weeks, lacking much of the dysfunction. This approach has yet to be earnestly tested as a way to help slow the progression of neurodegeneration, but the research community appears to be slowly moving in that direction.
It is evident that microglia are crucial players in the pathogenesis of Alzheimer's disease (AD), and a deeper understanding of their diverse functions and interactions with other cellular components in the brain will be vital for the development of effective therapeutic strategies. However, despite considerable progress in recent years, there remain significant gaps in our knowledge of microglial biology, particularly concerning their heterogeneity, precise mechanisms of action, and the interplay between various signaling pathways.
Multiple research studies have underscored the significance of specific subsets of microglia, particularly disease-associated microglia (DAM), in the progression of AD. The conjecture underpinning microglial depletion is that certain activated microglia, including DAM, may accentuate AD pathogenesis through a series of actions, such as facilitating the accumulation of Aβ plaques, amplifying neuroinflammation, and potentially influencing tau pathology. DAMs, characterized by a unique transcriptional profile and often found in close proximity to amyloid plaques, are thought to have substantial impacts on neuronal health and function. Consequently, it has been proposed that therapeutic strategies should be more disease-specific and aim at selectively targeting these DAMs.
The implementation of microglial depletion has been achieved through various strategies, most notably using pharmacological and genetic techniques. A common method involves the use of brain-penetrating inhibitors of CSF1R, a crucial cell surface receptor for microglial survival and proliferation. In AD mouse models, these inhibitors have demonstrated improvements in cognition and reductions in both neuroinflammation and neuritic plaque formation. However, the relationship between microglial depletion and amyloid pathology has been inconsistent, highlighting the need for further investigation. The potential of microglial depletion as a therapeutic approach must be carefully evaluated, but more research is warranted to further elucidate the complex roles of microglia, particularly DAM, in AD pathogenesis and treatment.