Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody

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.

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

“…Recent studies demonstrate that microglia are involved in the uptake of tau protein. In primary cultures of microglia (Luo et al, 2015; Bolós et al, 2016) and P301S mice (Luo et al, 2015), microglia internalize extracellular soluble and insoluble tau in vitro and in vivo , respectively. Thus, microglia seem to play a protective mechanism in the clearance of tau.…”

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

“…Therefore, it is likely that most of the phospho-tau in our S1 fractions were originally located intraneuronally. However, it is also known that microglia cells could phagocytose apoptotic tau-bearing neurons [29, 35]. Thus, we also tested whether intracellular phospho-tau could be toxic for microglia after phagocytosis.…”

“…Sarkosyl-insoluble tau was isolated as described [29]. Human hippocampi were homogenized in “homogenization buffer” (10 mM Tris, 0.8 M NaCl, 1 mM EGTA, 10 % sucrose, pH 7.4, plus protease, and phosphatase inhibitors).…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…Targeting numerous other epitopes has been shown to be effective in several studies. These include non-phosphorylated- [27,30,32,41,42,46–48,69,70], phosphorylated- [20,24,25,27,29,35,39,43,49], conformational-/oligomeric [20,31,33,34,40,44,45], and a truncated epitope [66,71]. Since these studies have various designs, they cannot be easily compared to identify the best epitopes to target.…”