BBB Dysfunction Defines the Aging Myeloid Landscape Favoring Immune Evasion for Glioma and Alzheimer's Disease

Abstract The blood-brain barrier (BBB) defines the physiological function of the brain, and it is disrupted in multiple neuropathological diseases. Although vascular abnormalities and BBB leakage characterize the progression of gliomas and occurs in the early stages of Alzheimer's disease (AD), it is unclear their correlation with the neurodegeneration observed in the brain parenchyma. Here, molecular analysis of the brain’s ecosystem showed that gene expression signatures linked to BBB dysfunction and neuronal synapses correlate directly and inversely, respectively, with the progression of AD and gliomas. Using human samples, patient´s-derived xenografts and mice with orthotopically implanted glioma cells, we observed that neuronal loss is linked to BBB breakdown in mesenchymal tumors. This involves the extravasation of monocyte-derived macrophages, specifically those with a suppressive phenotype, in tandem with a surge of inflammatory cytokines. Moreover, our data demonstrate that vascular normalization can revert the neuronal loss and the aggressiveness in those gliomas. Overall, we propose that BBB dysfunction is a common process associated with aging that drives chronic inflammation, which is governed by TREM2+/TIM3+ suppressor myeloid cells. These results could help us to apply therapies to the progression of central nervous system pathologies that are associated with the aging process, with the hallmarks of toxic neuroinflammation and myeloid dysfunction.