Abstract
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-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.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.
Highlights
Misfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer’s disease (AD)
Comparison among three or more groups was performed by Isolated microglia are relatively pure and do not express the tau gene In order to determine purity of cells isolated by CD11b magnetic microbead isolation, we performed Quantitative real-time PCR (qPCR) on isolated microglia from pooled wild type (WT) and rTg4510 microglia (Fig. 1b)
We examined microglia-conditioned media (CM) from rTg4510 mice and found that their media contained significantly more human tau protein compared to WT microglia on DIV3 and DIV6 (p < 0.001) and DIV9 (p < 0.01) as quantified by two-way Analysis of variance (ANOVA) with a Bonferroni post-hoc test Fig. 2d), which tapered off over time in vitro, demonstrating that microglia releases tau in vitro but do not generate more during that time
Summary
Misfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer’s disease (AD). Recent studies as well as the data contained suggest that microglia, the resident immune cells of the central nervous system, play a direct role in the spread of tau pathology. Microglia are the resident immune cells of the central nervous system (CNS) and are the primary mediators of neuroinflammation, which is an important component mechanism of neurodegeneration during Alzheimer’s disease (AD). In contrast to our data previous studies have shown that microglia are capable of degrading tau most efficiently, or possibly only, when they are activated via Fc/antibody- or lipopolysaccharide- (LPS) mediated mechanisms [35, 36]
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