LRP1 Triggers Pro-inflammatory Cell-signaling in Response to Extracellular Tau Independently of the NMDA Receptor

Abstract

In Alzheimers Disease (AD) and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates. The mechanisms by which Tau may promote AD progression remain incompletely understood. Injured and dying neurons release Tau into the extracellular spaces in the CNS. The released Tau may be taken up by receptors in the LDL Receptor gene family, including Low Density Lipoprotein Receptor-related Protein-1 (LRP1), which is expressed by microglia, astrocytes, and neurons. This process may be important for clearing Tau from extracellular spaces but may also promote the seeding of Tau aggregates in new cells. Our laboratory has shown that endocytosis of LRP1 ligands is coupled to the activation of cell-signaling and regulation of inflammation. Notably, different LRP1 ligands can induce either pro-inflammatory or anti-inflammatory responses, depending on the co-receptors that function with LRP1. Here, we demonstrate that in cultured macrophages, microglia, and astrocytes, extracellular Tau induces an LRP1-dependent pro-inflammatory response, characterized by NF{kappa}B activation and expression of pro-inflammatory cytokines. Unlike other LRP1 ligands that elicit anti-inflammatory responses, the response to Tau occurs independently of the NMDA receptor. When LRP1 is deleted or silenced, macrophages, microglia, and astrocytes do not respond to Tau, whereas when Grin1 is deleted or the NMDA-R is pharmacologically inhibited, the responses remain unchanged. Because we have evidence that LRP1 in microglia expresses anti-inflammatory activity in response to ligands other than Tau, understanding the role of LRP1 in microglia and astrocytes in vivo in Alzheimers Disease and other neuroinflammatory processes is an important future goal. SIGNIFICANCE STATEMENTIn Alzheimers Disease and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates that contribute to disease progression. When released extracellularly, Tau binds to the transmembrane receptor LRP1, expressed by diverse cells in the CNS. LRP1 has the unique ability to couple ligand uptake with activation of cell-signaling. We demonstrated that Tau binding to LRP1 activates pro-inflammatory responses in macrophages, microglia, and astrocytes, characterized by NF{kappa}B activation and cytokine release. This signaling occurs independently of the NMDA receptor, which distinguishes Tau from other LRP1 ligands. These results define a novel pathway by which extracellular Tau regulates neuroinflammation in Alzheimers Disease, providing new therapeutic opportunities that target LRP1 without interfering with NMDA-R functions.