The project led by Dr. Stevens focuses on the role of brain border-associated macrophages (BAMs) in neuroinflammation following a peripheral immune response. BAMs are a unique type of immune cell located at the brain’s borders near blood vessels and the protective membrane layers that encase the brain. Unlike microglia, which serve as innate immune sentries and housekeepers only within the brain, BAMs monitor and clean up material from both the brain and periphery. Recent research indicates that these cells could play a role in amyloid beta build-up during Alzheimer’s disease. Preliminary findings from the Stevens lab suggest that with age, BAMs become more inflammatory and less effective at clearing debris or pathogens. The team hypothesized that peripheral inflammation influences the function of BAMs and that dysfunctional BAMs contribute to Alzheimer’s-related pathologies by altering neuron-glia crosstalk in the brain.
The Stevens lab is pursuing three experimental aims using advanced cell sorting, sequencing, imaging, mouse genetic methods, and human samples. The first aim is exploring how peripheral inflammation influences BAM numbers and their ability to engulf and clear amyloid pathologies in an amyloid mouse model. The second aim is investigating the specific molecules and signaling pathways affected by peripheral inflammation in various cell types located at the brain’s borders. In the third aim, they are identifying molecules involved in neuroimmune interactions in humans, using a unique cohort of people with and without early-stage Alzheimer’s disease. This cohort includes samples with border cells, blood, cerebrospinal fluid, and brain tissue from the same individuals.
The team made significant progress in their first year of funding across all three aims. They identified that mouse BAMs exhibit higher amyloid engulfment rates than do microglia and confirmed the same is true in human BAMs and microglia. An unexpected outbreak of C. bovis in their mouse colony provided an opportunity for the Stevens lab to investigate the effects of systemic infection on BAMs, and they discovered that the inflammation reduced amyloid engulfment by BAMs but not by microglia, revealing compartment-specific immune responses in their AD mouse model. They also identified a population of scavenger cells enriched with AD genes, which lose their engulfment abilities with aging and inflammation. These findings suggest that impaired BAM function may be a critical driver of AD onset and progression. In the next phase, the team will refine their functional assessments and integrate data from mouse models, cell studies, and human samples to further explore these mechanisms.
