Picture an aggressive case of food coma. Microglia that noshed on tau-laden neurons soon regurgitated the aggregates, lost their appetites, and sank into a nefarious slumber, Maria Grazia Spillantini and Aviva Tolkovsky of the University of Cambridge, U.K., reported October 22 in Science Advances. Only when microglia consumed neurons riddled with tau tangles—not tau fibrils alone—did the cells undergo this transformation. The scientists found evidence of similar phenomena in the brains of people who had died with tauopathies, and of mice that overexpressed tau. They propose that dysfunctional microglia are part of a vicious cycle that exacerbates tauopathies.
- After ingesting neurons containing tau aggregates, microglia spat out tau seeds.
- They also stopped phagocytosis.
- The microglia took on a senescent phenotype, including expression of metalloprotease.
Previously, Spillantini had found that, when overloaded with tau aggregates, neurons flipped lipids in their cell membranes, exposing phosphatidyl serine to the extracellular space. This inversion is a sign of impending apoptosis. It baited microglia to devour the neurons, tau aggregates and all, in a phagocytic binge (Aug 2018 news).
How did these microglia fare, postprandially? First author Jack Brelstaff and colleagues tackled this question in the current study. They started by co-culturing dorsal root ganglia neurons from 5-month-old P301S-tau mice with microglia from wild-type neonatal mice. As they had reported previously, microglia readily gobbled up the tau-ridden neurons. Curiously, the researchers also detected tau aggregates floating in the culture medium, but only when microglia were present. This hinted that tau was being released from the microglia, not from the P301S neurons. Indeed, after Brelstaff separated microglia from their neuronal prey, the glia continued to spew out tau aggregates for at least four more days.
Importantly, the tau the microglia released was an insoluble, fibrillar form that seeded aggregation of normal, soluble tau in biosensor cell lines.
Had bits of the tau-laden neurons made the microglia sick? It seems so, because the cells lost their appetites. When offered more P301S neurons, or latex beads, a commonly used phagocytotic bait, the cells did not imbibe. Oddly, neither tau aggregates nor phosphatidyl serine liposomes alone pushed microglia into this hypophagic state, suggesting that taking bites out of a tau-bearing neuron was required to sate-and-sedate the microglia. The researchers found evidence of a similar phenomenon in mouse brain: microglia in cortical slices from P301S mice consumed fewer latex beads than did microglia in slices from wild-type animals (see image below).
What factors within the neurons cause microglia to spew tau seeds and shut down phagocytosis? This is the subject of ongoing work, Spillantini and Tolkovsky said.
Because the microglia shut down phagocytosis, the researchers wondered if the cells might be senescent. Indeed, these microglia tripled production of β-galactosidase, a biomarker of senescence, compared to microglia that mingled with wild-type neurons. Interestingly, this senescence marker also appeared in naïve microglia exposed to the medium from P301S neuron/microglia co-cultures, but not medium from P301S neurons alone. This suggested that a soluble factor released by microglia that had internalized P301S neurons was able to instigate a senescent phenotype in other microglia in a paracrine fashion.
Senescent glial cells crank out damaging cytokines and proteases, and their accumulation has been implicated in neuronal death in tauopathy models (Streit et al., 2009; Sep 2018 news). To see if these tau-spewing microglia also release other toxic cargo, the researchers surveyed the cell medium. They found that microglia co-cultured with P301S neurons secreted a unique profile of proteins. Eleven were distinct from those cranked out by microglia exposed to lipopolysaccharide or to wild-type neurons. These included two matrix metalloproteinases, MMP3 and MMP9; three chemokines, CXCL2, CXCL1, and CCL5; and IGFBP3, a growth factor previously pegged as part of the senescence-associated secretory phenotype.
MMP3 stood out as most elevated, so the researchers focused on its regulation. They ultimately found that MMP3 expression depended on NfκB. Notably, MMP3 could be induced in microglia-neuron co-cultures even if the authors blocked phagocytosis, suggesting that a soluble factor in the co-cultures triggered the senescent phenotype.
Did this microglial phenotype emerge in the tauopathy-ravaged brain? Using MMP3 as a proxy, the researchers examined wild-type mice and 2-month-old P301S mice that had not yet developed tau pathology. They detected both the inactive, zymogen form of MMP3, as well as the active, mature form, in both. However, in 5-month-old P301S, which had rampant tau aggregates, levels of active protease had tripled.
The scientists also found that people with frontotemporal dementia caused by tau mutations, Pick’s disease, or progressive supranuclear palsy had up to fourfold more MMP3 in their brains at postmortem. Active MMP3 was also elevated in one person with FTD caused by the C9ORF72 mutation, which causes accumulation of TDP-43 rather than tau.
Slide Into Slumber. This model proposes that microglia become hypophagic and senescent after feasting on neurons with tau aggregates in them. The microglia then “vomit” tau seeds, which spread pathology, and cytokines, which lull other microglia into senescence. [Courtesy of Brelstaff et al., Science Advances, 2021.]
In all, the findings suggest that when microglia ingest tau aggregates, they become unwitting sowers of tau seeds in the brain. At the same time, the cells shirk phagocytosis and drive senescence in adjacent microglia, feeding a vicious cycle that could exacerbate tauopathy (see image above).
“The study will shed new light on our understanding of tau propagation in glia and non-synaptic mechanisms,” commented Tsuneya Ikezu of the Mayo Clinic in Jacksonville, Florida. Ikezu’s group previously proposed that after engulfing tangle-containing neurons, microglia help disseminate tau by packaging it into extracellular vesicles (Delpech et al., 2019). Ikezu added that his lab also observed secretion of free-form tau aggregates by microglia.
Diego Gómez-Nicola of the University of Southampton, U.K., noted that it remains unclear exactly how the neurons change the microglia, and how those changes are related to each other. “Is senescence triggered first, leading to defective phagocytosis, or is indigestion caused by over phagocytosis of tau leading to senescence,” Gómez-Nicola asked?
The new findings validate previous studies implicating tau in induction of microglial senescence (Bussian et al., 2021). Aβ, too, has been tied to microglial senescence as well as to the concept of “frustrated phagocytosis.” Gómez-Nicola said the new tau findings jibe with evidence from his group that Aβ pathology both invokes and is exacerbated by microglial senescence (Jun 2021 news).
The study highlights that sleepy microglia are capable of causing trouble, noted Kiran Bhaskar and Gary Rosenberg of University of New Mexico, Albuquerque. “Despite adopting two functionally deficient phenotypes—hypophagy and senescence—the microglia still activate NFκB and secrete tau seeds,” they wrote. They recently reported that tau tangles switch on Nfκb in microglia (Jiang et al., 2021).—Jessica Shugart
- Tangles Turn Neuronal Membranes Inside Out, Give Microglia License to Eat Their Fill
- Are Tauopathies Caused by Neuronal and Glial Senescence?
- DAMned to Death? Microglia May Proliferate to Senescence
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No Available Further Reading
- Brelstaff JH, Mason M, Katsinelos T, McEwan WA, Ghetti B, Tolkovsky AM, Spillantini MG. Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates. Sci Adv. 2021 Oct 22;7(43):eabg4980. Epub 2021 Oct 20 PubMed.