Abstract
Microglia have been shown to contribute to the clearance of brain amyloid β peptides (Aβ), the major component of amyloid plaques, in Alzheimer’s disease (AD). However, it is not known whether microglia play a similar role in the clearance of tau, the major component of neurofibrillary tangles (NFTs). We now report that murine microglia rapidly internalize and degrade hyperphosphorylated pathological tau isolated from AD brain tissue in a time-dependent manner in vitro. We further demonstrate that microglia readily degrade human tau species released from AD brain sections and eliminate NFTs from brain sections of P301S tauopathy mice. The anti-tau monoclonal antibody MC1 enhances microglia-mediated tau degradation in an Fc-dependent manner. Our data identify a potential role for microglia in the degradation and clearance of pathological tau species in brain and provide a mechanism explaining the potential therapeutic actions of passively administered anti-tau monoclonal antibodies.
Highlights
With anti-tau monoclonal antibodies reduces age-dependent tau pathology in these mouse tauopathy models is poorly understood
In our study we demonstrate that murine microglia can efficiently internalize and degrade pathological tau species derived from human Alzheimer’s disease (AD) and P301S transgenic mouse brain
The ability of microglia to internalize and degrade tau is enhanced by the anti-tau monoclonal antibody MC1 via an Fc-dependent mechanism, revealing a potential mechanism for antibody-based tau immunotherapy
Summary
Microglia rapidly internalize and efficiently degrade sarkosyl-insoluble tau in a time-dependent manner. No significant decrease in the levels of either brain-released total tau or AT8-positive tau was observed in MCM comparing to normal medium following 24 hrs incubation (p = n.s.; Fig. 2d) These results suggest that enzymes secreted from microglia contribute little if any to microglial-induced tau degradation and that the presence of microglia (and likely the internalization of tau) is necessary for tau degradation. After primary microglia were incubated with SI-tau in the presence or absence of MC1 or a control mouse IgG (non-immunized), a significant enhancement of microglial-dependent tau degradation (for both total tau and AT8 positive-tau) was observed in a time-dependent manner in the presence of MC1 compared to the IgG control antibody (Fig. 4a). These results suggest that Fc effector function is necessary for the antibody-enhanced internalization and degradation of tau by microglia
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