Dr. Blurton-Jones’ project addresses a long-standing and highly debated question in neuroimmunology: do immune cells from the bloodstream infiltrate the aging or Alzheimer’s brain, and if so, do they contribute to disease progression? Microglia, the brain’s resident immune cells, arise early in development and maintain themselves throughout life. In contrast, monocytes and other peripheral immune cells are continuously generated from the bone marrow. While studies in mice and analyses of human transplant samples suggest that peripheral monocytes can enter the brain during aging and disease, it remains unclear whether these infiltrating cells are protective, neutral, or harmful in Alzheimer’s disease.
Recent work from this lab using innovative humanized mouse models demonstrated that brain-engrafted human monocytes adopt a chronic proinflammatory state distinct from that of microglia. Monocyte engraftment was associated with increased inflammatory signaling, loss of synaptic and myelin proteins, and neuronal vulnerability—changes not observed with human microglial engraftment. These findings suggest that the developmental origin of immune cells—microglia versus monocytes—may fundamentally shape their impact on brain health.
The central hypothesis of this project is that infiltration of peripheral human monocytes promotes tau pathology and neurodegeneration in AD. To test this, the Blurton-Jones team will directly compare the effects of brain-engrafted human monocytes and microglia on tau-associated neurodegeneration using newly developed chimeric tauopathy mouse models that allow full replacement of the microglial niche with human cells. They will determine whether monocyte engraftment accelerates tau hyperphosphorylation, astrogliosis, synaptic loss, and neuronal degeneration relative to microglial engraftment. The team will also examine whether APOE genotype influences the rate of monocyte infiltration into the brain and whether APOE4-derived monocytes exacerbate tau pathology and neurodegeneration. Finally, they will apply newly defined transcriptional signatures that distinguish monocytes from microglia to postmortem human brain samples to determine whether increased peripheral monocyte infiltration correlates with Alzheimer’s pathology and cognitive impairment.
Through close collaboration with partners from the Neuroimmune Consortium, the Blurton-Jones lab will integrate findings on astrocyte reactivity, antigen presentation, synaptic loss, and epigenetic programming to determine how monocyte origin and activation state influence disease trajectories. By clarifying whether age- or genotype-dependent recruitment of peripheral monocytes contributes directly to tau pathology and neurodegeneration, this work addresses a central unanswered question in the field and may reveal new opportunities to modulate harmful immune cell infiltration in AD.
