Pathological Tau Regulates Autophagy and Inflammation in Microglia
Poster presented at the Brain & Behavioral Health Research Day 2023
Abstract
Hyperphosphorylated tau monomers and its conformers - oligomer, paired helical filaments (PHFs), and neurofibrillary tangles (NFTs) can be cleared by brain-resident immune cells “microglia”. However, microglial function is dysregulated in Alzheimer’s disease (AD) and other tauopathies, causing “cytokine storm” and spreading of protein aggregation in various regions of the brain. Autophagy is well known for its anti-inflammatory function by degrading inflammasome components besides its role in protein homoeostasis, which is impaired in neurodegenerative diseases. Here, we found impaired autophagy (accumulation of p62 and LC3II) in human microglial cell line and iPSC-derived human microglia cells (iMGLs) treated with lysates from hTau, but not non-transgenic, mouse brain, and purified tau monomer. Surprisingly, a canonical inflammatory NF-kB pathway inhibitor protein, IkBα was also coincidentally accumulated, suggesting that autophagy likely regulates NF-kB-inflammation. Next, mouse bone marrow macrophage cells (BMM) treated with human tau oligomers and PHFs showed accumulation of galectin 3 (marker of endo-membrane damage) and p62 (autophagy receptor) puncta, suggesting that endocytosed pathological tau damages membranous vesicles or intracellular organelles. Activation of inflammatory NF-kB pathway by pathological tau was also confirmed by NF-kB luciferase reporter assay in mouse microglia BV2, astrocyte C8D1A, and BMMs. Together, these results suggest the gain-of-toxic-function of tau in driving NF-kB-mediated inflammation via impairing autophagy.
