The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease
Abstract Background Misfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer’s disease (AD). Tau pathology correlates with cognitive decline in AD and follows a stereotypical anatomical course; several recen...
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doaj-b5c4cd4eb1524b6e967f84764785eb352020-11-24T22:12:33ZengBMCJournal of Neuroinflammation1742-20942018-09-0115111510.1186/s12974-018-1309-zThe role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s diseaseSarah C. Hopp0Yang Lin1Derek Oakley2Allyson D. Roe3Sarah L. DeVos4David Hanlon5Bradley T. Hyman6Alzheimer’s Disease Research Laboratory, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical SchoolNortheastern UniversityAlzheimer’s Disease Research Laboratory, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical SchoolAlzheimer’s Disease Research Laboratory, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical SchoolAlzheimer’s Disease Research Laboratory, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical SchoolQuanterix CorporationAlzheimer’s Disease Research Laboratory, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical SchoolAbstract Background Misfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer’s disease (AD). Tau pathology correlates with cognitive decline in AD and follows a stereotypical anatomical course; several recent studies indicate that tau pathology spreads inter-neuronally via misfolded tau “seeds.” Previous research has focused on neurons as the source of these tau seeds. However, recent studies as well as the data contained herein suggest that microglia, the resident immune cells of the central nervous system, play a direct role in the spread of tau pathology. Methods Primary adult microglia were isolated from human AD cases and the rTg4510 tauopathy mouse model and used for analysis of gene expression, tau protein by Simoa technology, and quantification of tau seeding using a highly sensitive fluorescence resonance energy transfer (FRET) biosensing cell line for tau seeding and aggregation. Results Here, we show that microglia isolated from both human tauopathy and AD cases and the rTg4510 tauopathy mouse model stably contain tau seeds, despite not synthesizing any tau. Microglia releases these tau seeds in vitro into their conditioned media (CM). This suggests that microglia have taken up tau but are incapable of entirely neutralizing its seeding activity. Indeed, when in vitro microglia are given media containing tau seeds, they reduce (but do not eliminate) tau seeding. When microglia are treated with inflammagens such as lipopolysaccharide (LPS), interleukin-1β (IL1β), tumor necrosis factor α (TNFα), or amyloid-β, their ability to reduce tau seeding is unchanged and these factors do not induce seeding activity on their own. Conclusions Overall, these data suggest that microglia have a complex role: they are capable of taking up and breaking down seed competent tau, but do so inefficiently and could therefore potentially play a role in the spread of tau pathology.http://link.springer.com/article/10.1186/s12974-018-1309-zTauMicrogliaAlzheimer’s disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sarah C. Hopp Yang Lin Derek Oakley Allyson D. Roe Sarah L. DeVos David Hanlon Bradley T. Hyman |
spellingShingle |
Sarah C. Hopp Yang Lin Derek Oakley Allyson D. Roe Sarah L. DeVos David Hanlon Bradley T. Hyman The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease Journal of Neuroinflammation Tau Microglia Alzheimer’s disease |
author_facet |
Sarah C. Hopp Yang Lin Derek Oakley Allyson D. Roe Sarah L. DeVos David Hanlon Bradley T. Hyman |
author_sort |
Sarah C. Hopp |
title |
The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease |
title_short |
The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease |
title_full |
The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease |
title_fullStr |
The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease |
title_full_unstemmed |
The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease |
title_sort |
role of microglia in processing and spreading of bioactive tau seeds in alzheimer’s disease |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2018-09-01 |
description |
Abstract Background Misfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer’s disease (AD). Tau pathology correlates with cognitive decline in AD and follows a stereotypical anatomical course; several recent studies indicate that tau pathology spreads inter-neuronally via misfolded tau “seeds.” Previous research has focused on neurons as the source of these tau seeds. However, recent studies as well as the data contained herein suggest that microglia, the resident immune cells of the central nervous system, play a direct role in the spread of tau pathology. Methods Primary adult microglia were isolated from human AD cases and the rTg4510 tauopathy mouse model and used for analysis of gene expression, tau protein by Simoa technology, and quantification of tau seeding using a highly sensitive fluorescence resonance energy transfer (FRET) biosensing cell line for tau seeding and aggregation. Results Here, we show that microglia isolated from both human tauopathy and AD cases and the rTg4510 tauopathy mouse model stably contain tau seeds, despite not synthesizing any tau. Microglia releases these tau seeds in vitro into their conditioned media (CM). This suggests that microglia have taken up tau but are incapable of entirely neutralizing its seeding activity. Indeed, when in vitro microglia are given media containing tau seeds, they reduce (but do not eliminate) tau seeding. When microglia are treated with inflammagens such as lipopolysaccharide (LPS), interleukin-1β (IL1β), tumor necrosis factor α (TNFα), or amyloid-β, their ability to reduce tau seeding is unchanged and these factors do not induce seeding activity on their own. Conclusions Overall, these data suggest that microglia have a complex role: they are capable of taking up and breaking down seed competent tau, but do so inefficiently and could therefore potentially play a role in the spread of tau pathology. |
topic |
Tau Microglia Alzheimer’s disease |
url |
http://link.springer.com/article/10.1186/s12974-018-1309-z |
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