BBB dysfunction drives neurotoxic myeloid cells in glioblastoma and Alzheimer’s disease

Abstract

Background The blood-brain barrier (BBB) defines the physiological function of the brain and is disrupted in multiple neuropathological diseases. Although vascular abnormalities and BBB leakage characterize glioma progression and occurs in the early stages of Alzheimer's disease (AD), their correlation with the neurodegeneration observed in the brain parenchyma is unclear. Methods Using RNAseq, bioinformatics tools and a cohort of patients with Glioma and Alzheimer's disease for validation of results, we have established an analysis of BBB dysfunction and neuron loss. A mouse model for GBM pathology was also used that reversed BBB disruption and neuron loss, with the incorporation of the IDH mutation. Finally, to establish a characterization of the relevant immune populations with an IHC analysis and transcriptional profile. Results 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, particularly in mesenchymal tumors. This involves the extravasation of monocyte-derived macrophages, specifically those with a suppressive phenotype, along with an increase in inflammatory cytokines. Moreover, our data demonstrate that vascular normalization can revert the neuronal loss and aggressiveness in these gliomas. Conclusions We propose that BBB dysfunction is a common brain process that drives chronic inflammation, governed by suppressive myeloid cells. These results could help us to apply common therapies to the progression of central nervous system pathologies associated with BBB dysfunction, since it functions as an enhancer through toxic neuroinflammation and myeloid dysfunction.