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

Abstract

In Alzheimer’s Disease (AD) and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates. Mechanisms by which Tau may promote AD progression remain incompletely understood. Low Density Lipoprotein Receptor-related Protein-1 (LRP1) mediates the uptake of Tau, which is released into the extracellular spaces in the brain and may thereby promote seeding of Tau aggregates in new cells. Herein, we demonstrate that in macrophages, microglia, and astrocytes, extracellular Tau induces an LRP1-dependent pro-inflammatory response, characterized by NFκB activation and expression of diverse pro-inflammatory cytokines. Unlike other LRP1 ligands that elicit LRP1-dependent cell-signaling events, the response to Tau occurs independently of the NMDA Receptor. Instead, Tau-activated cell-signaling requires the low affinity Neurotrophin Receptor (p75NTR). The role of p75NTRin Tau-elicited cell-signaling was demonstrated by gene-silencing and/or with TAT-Pep5, in macrophages, astrocytes, and PC12 cells. Because RhoA is activated downstream of p75NTR, we studied two Rho kinase pharmacologic inhibitors, Y-27632 and Fasudil Hydrochloride, and demonstrated that both reagents block NFκB activation and cytokine expression in response to Tau. These results define Tau and its receptor assembly, which includes LRP1 and p75NTR, as a novel biochemical system that may regulate neuro-inflammation in AD and other neurodegenerative diseases. The ability of Rho kinase inhibitors to antagonize the Tau-LRP1/p75NTRpathway may represent a novel mechanism by which these agents demonstrate efficacy in Alzheimer’s Disease.Significance StatementIn Alzheimer’s Disease and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates that contribute to disease progression. When Tau is released by cells, it binds to the transmembrane receptor, LRP1, which is expressed by diverse cells in the CNS. LRP1 has a unique ability to couple endocytosis with activation of cell-signaling. We demonstrated that Tau-binding to LRP1 activates pro-inflammatory responses in macrophages, microglia, and astrocytes. p75 Neurotrophin Receptor served as an essential co-receptor. Targeting Rho kinase, downstream of p75NTR, blocked Tau-initiated pro-inflammatory responses. These results define a novel pathway by which Tau may regulate neuro-inflammation in Alzheimer’s Disease and other neurodegenerative diseases.