In vitro generation of tau aggregates conformationally distinct from parent tau seeds of Alzheimer's brain.
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ABSTRACT:
SUBMITTER: Nam WH
PROVIDER: S-EPMC6422395 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Publications
In vitro generation of tau aggregates conformationally distinct from parent tau seeds of Alzheimer's brain.
Nam Won-Hee WH Choi Young Pyo YP
Prion 20181114 1
Normal monomeric tau can be converted into pathogenic aggregates and acquire protease resistance in a prion-like manner. This acquisition of partial protease-resistance in tau aggregates has to date only been partially investigated in various studies exploring the prion-like properties of tau. In this study, we induced the aggregation of tau repeat domain (RD) in cultured cells using detergent insoluble fractions of Alzheimer's brain tissue as seeds. The seeded aggregation of tau RD in cultured ...[more]
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Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
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Project description:BackgroundMisfolding 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.MethodsPrimary 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.ResultsHere, 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-1? (IL1?), tumor necrosis factor ? (TNF?), or amyloid-?, their ability to reduce tau seeding is unchanged and these factors do not induce seeding activity on their own.ConclusionsOverall, 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.
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