The project led by Dr. Blurton-Jones investigates the role of blood monocyte-derived macrophages (MDMs) in brain inflammation and the formation of amyloid plaques after peripheral inflammation. MDMs are peripheral immune cells, and there is evidence that they migrate into the brain during Alzheimer’s disease and take on microglial functions. However, it has been difficult to establish this with current methodologies and, thus, tricky to model for experiments. To address this challenge, the Blurton-Jones team is using a novel mouse model known as FIRE mice, which lack all mouse microglia. They have transplanted human-derived immune cells (microglia and MDMs) into the brains of these mice and then bred them with 5xFAD mice to induce amyloid pathology. This model allows the Blurton-Jones team to test key questions about the different roles and interactions of peripheral MDMs and brain microglia after peripheral inflammation and in the presence of amyloid pathologies. In previous research, the Blurton-Jones team established the baseline response and states of human microglia and MDMs after transplantation. They found that human MDMs respond and look very different than microglia because the MDMs adopt a proinflammatory state.
The team hypothesized that blood MDMs enter the brain during Alzheimer’s disease and cause both positive and negative effects on amyloid pathology and neuron functions. They are pursuing three aims to address their hypothesis. First, they are investigating how transplanted human MDMs and microglia respond to peripheral inflammation. Second, they are measuring how amyloid beta impacts the activation states of MDMs and microglia. Third, they are developing methods to accurately and reliably determine whether more MDMs are present in post-mortem brain samples from individuals with Alzheimer’s compared to healthy controls.
In their first year, the team achieved promising progress. Under their first aim, they discovered that transplanted MDMs maintain a chronic proinflammatory signature even without peripheral inflammation and produce molecules linked to harmful effects on neurons and cognition. In contrast, microglia transplanted into FIRE mice showed a healthier, more balanced homeostatic state. When exposed to peripheral inflammation, both cell types shifted toward a proinflammatory profile, but the response was more pronounced in microglia, highlighting their dynamic ability to adapt to peripheral inflammatory signals. In comparison, MDMs, already in a proinflammatory state, showed relatively muted changes. These findings suggest that brain-resident microglia are more active in responding to inflammation, while MDMs may contribute to a persistently inflamed environment. In the coming year, the team will prioritize aims two and three.
