Microglia revealed as double agents in Alzheimer’s disease progression
Researchers have identified that microglia first help spread Alzheimer’s disease pathology across the brain and then activate to limit its neurodegenerative effects.
Researchers from the VIB-KU Leuven Center for Brain and Disease Research (Belgium) and collaborating institutions have recently identified the opposing roles of brain-resident immune cells called microglia at different stages of Alzheimer’s disease (AD). Using a microglia-depleting drug and AD mouse models, they identified that microglia have a neuroprotective effect in late disease. However, in early disease, microglia played a key role in spreading AD pathology. Resolving the complex role of microglia in AD development has the potential to lead to improved therapeutic approaches.
Alzheimer’s disease is partially characterized by the formation of extracellular plaques of the amyloid-beta peptide (Aβ) in the brain. These plaques can begin forming decades before symptoms of AD appear. Genome-wide association studies have identified several high-risk variants for developing AD expressed by microglia. These cells remain inactive in healthy brains but activate upon detecting molecular patterns such as Aβ plaques. Attempts to identify the role of microglia in AD development and progression have yielded mixed and often contradictory results. To resolve these findings, researchers hypothesized that microglia perform different roles at different stages of AD progression.
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To test this hypothesis, the microglia-depleting drug PLX3397 was administered to an AD mouse model at different ages and disease stages. Mice treated between 1 and 4 months exhibited significantly fewer amyloid plaques compared to controls. This indicates that microglia play an important role in seeding Aβ plaques in the brain early in AD development. Mice treated between 3–7 months, following the establishment of Aβ plaques, did not show a significant decrease in Aβ plaques compared to the control. However, in the control mice, the plaques were much smaller and less diffuse, and associated damage to surrounding neurites was reduced. This suggests that in later disease stages, although microglia do not clear Aβ plaques, they play a role in compacting them, limiting their effects.
To confirm these findings and ensure that they were not the result of an off-target effect of PLX3397, another AD mouse model was generated in which microglia were not present. These mice, referred to as FIRE mice in the study, exhibited significantly fewer Aβ plaques compared to a control with functional murine microglia at 3 months. However, when FIRE mice underwent xenotransplantation with human-derived progenitor cells to allow human microglia to populate their brains, Aβ plaque formation was partially restored.
Following this, to identify the significance of activation status on the role of microglia in AD development, FIRE mice received human microglia modified to be consistently inactive. In a younger cohort of these mice, microglia-associated Aβ plaque seeding still occurred. However, in older mice, Aβ plaque compaction and neurite damage limitation were not observed. This demonstrates that inactive microglia play a key role in early Aβ plaque pathology, while activated microglia work to limit the neurodegenerative impact of Aβ plaques following their formation.
While Aβ plaque formation has long been identified as key in the pathogenesis of AD, treatments with significant clinical success targeting this phenomenon have remained elusive. This suggests that the process of plaque formation is controlled by many complex factors. This research has gone someway to untangle these factors and could be applied to the development of future AD drugs. “These findings clarify conflicting reports, confirm microglia as key drivers of amyloid pathology, and raise questions about optimal therapeutic strategies for the disease,” elaborated Bart De Strooper, corresponding author of this study.
