Aggregated tau‐phf6 (Vqivyk) potentiates nlrp3 inflammasome expression and autophagy in human microglial cells

Abstract

Intra‐neuronal misfolding of monomeric tau protein to toxic β‐sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progres-sive dementia but also with microglia‐mediated inflammation in AD. Amyloid‐beta (Aβ), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD‐like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleu-kin‐1β (IL1β) and interleukin‐18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau‐derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was ex-amined by qRT‐PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose-and time‐dependent manner, leading to increased expression of IL1β and IL18 in HMC3 cells. Aggregated PHF6‐peptide also activated other related inflammation and microglial polarization mark-ers. Furthermore, we also report a time‐dependent effect of the aggregated PHF6 on BECN1 (Beclin‐ 1) expression and autophagy. Overall, the PHF6 model system‐based study may help to better un-derstand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and micro-glial inflammation, polarization, and autophagy.