As you might be aware, the genetic differences present in Down syndrome patients produce a dramatic acceleration of amyloid-β aggregation, tau aggregation, and the other pathologies of Alzheimer's disease. Researchers here describe the discovery of a variant in the gene CSF2RB in a subset of Down syndrome patients that resist loss of cognitive function, and show that it improves the function of microglia. Microglia are innate immune cells resident in the brain. Increased inflammation and dysfunction in this cell population is strongly implicated in neurodegenerative conditions such as Alzheimer's disease. When equipped with the variant CSF2RB, microglia are less inflammatory and more capable when exposed to Alzheimer's-related protein aggregates - which may be enough to explain the resilience of patients with this gene variant.
Alzheimer's disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer's disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience.
Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4 to 10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence.
Thus CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies.
Link: https://doi.org/10.1038/s41593-025-02117-8
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