Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

Neurodegenerative diseases (ND) are characterized by a progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent dendritic cells that drive formation of lesions. Some patients with systemic LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by hematopoietic cells that are clonal with systemic LCH lesion histiocytes. Strikingly, we discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enabling migration of into the brain where they differentiate into senescent, inflammatory macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs synergistically reduced parenchymal infiltration, neuroinflammation and neurologic damage in preclinical LCH-ND. MAPK activation in circulating myeloid cells represents a novel and targetable mechanism of ND.