Glioblastoma-secreted soluble CD44 activates tau pathology in the brain

During aggressive tumor growth and migration, glioblastoma cells secrete diverse molecules and adhesion proteins to the extracellular matrix. Yet, the biochemical effects of the glioblastoma secretome in the brain remain largely unknown. Here we show that soluble CD44 secreted from glioblastoma cells induces neuronal degeneration through the activation of tau pathology in the brain. Glioblastoma-xenograft tissues showed a number of degenerating neurons bearing highly phosphorylated tau. Through a series of secretome-analyses, we identified that soluble CD44 was the responsible protein inducing tau phosphorylation and aggregation (EC 50 = 19.1 ng/mL). The treatment of sCD44 to primary hippocampal neurons-induced tau hyperphosphorylation, leading to neuronal degeneration. Also, the injection of sCD44 into the brains of tau transgenic mice induced tau hyper-phosphorylation in hippocampal neurons. Altogether, our data suggest a neurodegenerative role of sCD44 in promoting tau pathology and serving as a molecular link between glioblastoma and neurodegeneration. Brain tumors: Protein prompt for brain degeneration A protein secreted by aggressive brain tumors triggers the degeneration of neurons in surrounding brain tissues. The most aggressive brain tumors are formed by glioblastoma cells, which secrete molecules that infiltrate surrounding brain tissues, leading to loss of memory, communication and motor functions. Researchers led by Cheolju Lee and Yun Kyung Kim at the Korea Institute of Science and Technology in Seoul have shown that the CD44 protein, secreted by glioblastoma cells, is responsible for triggering this neurodegeneration. They discovered that sCD44 activates another process known as tau pathology, which is characteristic of multiple neuro-degnerative disorders such as Alzheimer’s disease. The tau protein usually stabilizes internal cellular structures, but when it is modified by abnormal activity such as the elevated levels of sCD44 found in this study, it forms insoluble masses, disrupting neuronal structure and function.