Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo

Abstract

The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons-a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer's disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.

Alzheimer’s disease as an inflammatory disease

“…Activated microglia are frequently present in the proximity of NFTs in the hippocampus of AD patients, thereby indicating a close relationship between the inflammatory response and tau neurofibrillary lesions. Furthermore, tau can be phagocytosed by microglia (67). This finding would support the notion that impaired clearance of extracellular tau (by microglia) contributes to the spread of pathological tau, as shown in AD (68).…”

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.…”

Glial contributions to neurodegeneration in tauopathies

“…Furthermore, tau lesions impact glial functions leading to an array of deleterious consequences both within the glia themselves as well as non-cell autonomous effects on neuronal health. Tau inclusions have also been reported in microglia [80–82] despite a lack of tau expression, providing further evidence that pathological tau may also be transferring between cells in the brain.…”

“…Microglia readily take up both soluble and insoluble forms of tau [7, 56, 82, 116]. Once engulfed, tau is either degraded [116] or re-released in exocytosing microvesicles called exosomes [7, 55].…”