Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells
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 progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide i...
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2021-06-01
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| author | Chinmaya Panda Clara Voelz Pardes Habib Christian Mevissen Thomas Pufe Cordian Beyer Sharad Gupta Alexander Slowik |
| author_facet | Chinmaya Panda Clara Voelz Pardes Habib Christian Mevissen Thomas Pufe Cordian Beyer Sharad Gupta Alexander Slowik |
| author_sort | Chinmaya Panda |
| collection | DOAJ |
| description | 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 progressive 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 interleukin-1β (IL1β) and interleukin-18 (<i>IL18</i>). 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 examined 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 <i>IL18</i> in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on <i>BECN1</i> (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy. |
| first_indexed | 2024-03-10T09:53:38Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T09:53:38Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4a3ba6f8057f45cc971a38580d4cc3942023-11-22T02:32:12ZengMDPI AGCells2073-44092021-06-01107165210.3390/cells10071652Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial CellsChinmaya Panda0Clara Voelz1Pardes Habib2Christian Mevissen3Thomas Pufe4Cordian Beyer5Sharad Gupta6Alexander Slowik7Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar 382355, IndiaInstitute of Neuroanatomy, Medical Faculty, RWTH Aachen University, 52074 Aachen, GermanyDepartment of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, GermanyInstitut für Organische Chemie, RWTH Aachen University, 52074 Aachen, GermanyDepartment of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen University, 52074 Aachen, GermanyInstitute of Neuroanatomy, Medical Faculty, RWTH Aachen University, 52074 Aachen, GermanyBiological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar 382355, IndiaInstitute of Neuroanatomy, Medical Faculty, RWTH Aachen University, 52074 Aachen, GermanyIntra-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 progressive 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 interleukin-1β (IL1β) and interleukin-18 (<i>IL18</i>). 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 examined 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 <i>IL18</i> in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on <i>BECN1</i> (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy.https://www.mdpi.com/2073-4409/10/7/1652Alzheimer’s diseasePHF6taumicrogliaHMC3autophagy |
| spellingShingle | Chinmaya Panda Clara Voelz Pardes Habib Christian Mevissen Thomas Pufe Cordian Beyer Sharad Gupta Alexander Slowik Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells Cells Alzheimer’s disease PHF6 tau microglia HMC3 autophagy |
| title | Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells |
| title_full | Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells |
| title_fullStr | Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells |
| title_full_unstemmed | Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells |
| title_short | Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells |
| title_sort | aggregated tau phf6 vqivyk potentiates nlrp3 inflammasome expression and autophagy in human microglial cells |
| topic | Alzheimer’s disease PHF6 tau microglia HMC3 autophagy |
| url | https://www.mdpi.com/2073-4409/10/7/1652 |
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