Tau Triggers Neuroinflammation, But Mechanisms Vary by Disease

Series - Tau2022 Global Conference (Virtual Meeting):

Inflammation flares up in the brain in all neurodegenerative diseases, but how so? At the Tau2022 conference, held virtually February 22-23, researchers elucidated some links between tauopathy and neuroinflammation. Jessica Rexach of the University of California, Los Angeles, compared primary tauopathies and Alzheimer’s disease, a secondary tauopathy, using both mouse and human data. She found strikingly different inflammatory profiles. In primary tauopathies, natural killer cells infiltrated the brain, whereas AD featured a microglial antiviral response orchestrated by interferon-γ. “Tauopathies invoke the immune response in different ways,” Rexach told Alzforum.

  • In two primary tauopathies, natural killer cells may contribute to brain damage.
  • In AD, genetic data implicate a microglial antiviral response.
  • Hyperexcitability triggered by tau could also boost neuroinflammation in AD.

Lennart Mucke of the Gladstone Institute of Neurological Disease, San Francisco, came at the question of tau and neuroinflammation from a different angle. He tied activated microglia in AD brain to the electrical imbalance caused by excessive tau. Lowering tau dampened excitation and suppressed many inflammation-related AD risk genes. “Epileptiform activity drives aberrant microglial responses,” Mucke concluded.

Some previous studies have blamed activated microglia for sparking tau pathology, but few have looked in the other direction, i.e., at how abnormal tau itself kicks off inflammation (Feb 2007 news; Oct 2019 news; Nov 2019 news).

Rexach earlier examined this in rTg4510 and TPR50 mice, which express human mutant P301L tau (Onishi et al., 2014). She purified microglia at different points along the disease course and analyzed their gene expression to identify co-expression modules that characterized each stage. These modules reflect the biological response of microglia to tauopathy as pathology worsens, Rexach told Alzforum. She then identified the same co-expression modules in published human transcriptomic data from AD brain, as well as in two primary tauopathies, progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD). This suggested the modules were relevant to human disease.

Notably, many risk genes for PSP and FTD fell into a single module characterized by the suppression of microglial viral defense genes. This module activates at early preclinical stages of tauopathy and includes genes like Trim21, which has been associated with the prion-like spread of proteins and has been linked to TDP-43 forms of FTD (Dec 2018 conference news). AD genes, on the other hand, popped up in a module that cranks up viral defense genes late in tauopathy, led by interferon-γ (Rexach et al., 2020). “We need to dig further into these parallels between tauopathy and viral response,” Rexach told Alzforum.

At Tau2022, Rexach added data on noncoding GWAS hits. She used chromosome conformation capture to predict what genes these noncoding risk variants affected. Again, the diseases diverged: PSP heritability affected genes involved in glia-lymphocyte interactions, particularly protection from natural killer cells, while AD heritability affected complement, cytokine, and myelin genes. Other studies have linked complement proteins to synapse loss in AD (Aug 2013 news; Dec 2014 news; Apr 2016 news).

Did brain tissue support this genetic dichotomy? In collaboration with Daniel Geschwind at UCLA, William Seeley at the University of California, San Francisco, and Dheeraj Malhotra at Roche, Rexach examined postmortem tissue from AD, PSP, and Pick’s disease brains. Pick’s disease is a subtype of FTD characterized by three-repeat deposits of tau, making it distinct from PSP, which has four-repeat tau. Tissue samples came from 40 brains and seven brain regions, comprising the angular gyrus, dentate of the cerebellum, insula, entorhinal cortex, globus pallidus, calcarine cortex, and precentral gyrus. These regions were selected because they each selectively degenerate in one or two of the three tauopathies, but not in the others. The researchers analyzed samples by both bulk and single-cell RNA-Seq.

The data dovetailed with Rexach’s previous findings. In PSP and Pick’s brain, single-cell data revealed the presence of infiltrating natural killer cells in the insula. These lymphocytes are cytotoxic, selectively attacking sick or damaged cells. Notably, in all regions of PSP brain, genes that protect against NK cells were suppressed. Meanwhile, in every region of Pick’s brain, the MICB gene that activates NK cells was massively expressed. Together the data suggest that in both PSP and Pick’s, brain tissue may become more vulnerable to cytotoxic damage from invading lymphocytes.

In addition, microglia in Pick’s brain had a distinct gene-expression profile driven by the transcription factor IKZF1. This gene is also active in lymphocytes and is pro-inflammatory, suggesting it could contribute to microgliosis in Pick’s.

In AD brain, by contrast, microglia displayed a familiar inflammatory profile driven by the SPI1 gene that encodes the master regulator protein PU.1. PU.1 controls AD risk genes and affects Alzheimer’s onset (Jun 2017 news).

AD microglia also expressed many genes found in mouse disease-associated microglia (DAM). Evidence for DAM in human brain has been mixed, with some studies not finding them and others reporting DAM genes scattered across several microglial subtypes (May 2019 news; Dec 2020 news). Intriguingly, Rexach found the strongest DAM signature in microglia around plaques in brain regions without much degeneration. This fits with a model in which DAM genes help microglia contain amyloid and ameliorate tissue damage (Jun 2017 news). In brain regions where the disease has advanced, microglia may lose this ability, Rexach suggested. She plans to follow up on these genetic data with functional studies in cellular and animal models.

While this study characterized the immune responses to tauopathy, it remains unclear how tau might trigger inflammation. Mucke provided some clues by focusing first on network activity. He has long been interested in links between tau and epileptic activity, and recently reported that deleting the protein in mice affects excitatory and inhibitory activity differently, with the former firing less and the latter firing more (Oct 2021 news). But which comes first?

At Tau2022, Mucke demonstrated that tau exerts its effects in excitatory cells. Conditionally deleting the protein only in excitatory neurons prevented epileptic activity after exposure to a stimulant, while deleting tau only in inhibitory neurons did not. The same thing happened when Mucke crossed these conditional knockouts with mice that model Dravet syndrome, which combines epilepsy and autism-like behaviors. Deleting tau in excitatory neurons ameliorated stereotyped behaviors and improved mouse survival to nearly wild-type levels, while deleting it in inhibitory neurons had no effect.

How might tau’s effect on excitation dovetail with autism-like behavior? Mucke and others previously reported that tau inhibits PTEN. This phosphatase suppresses a PI3 kinase pathway that promotes autism-like behavior. Network hyperactivity triggers this PI3K pathway, but when tau is absent, PTEN is able to intervene to dampen it. Excess tau, however, prevents PTEN from doing its job and leaves the brain vulnerable to hyperexcitability (Marciniak et al., 2017; Tai et al., 2020).

At Tau2022, Mucke reported massive activation of the PI3K pathway in the Dravet syndrome mice; dampening tau suppressed it. It is unclear how this mechanism relates to the selective vulnerability of excitatory neurons to tau. Mucke plans to dissect the molecular mechanisms to find out if PTEN or other pathway components are preferentially expressed in excitatory neurons.

And where does inflammation come in? Lowering tau in an amyloidosis mouse model also drops expression of many inflammation-related AD genes such as C1q, Tyrobp, and TREM2, suggesting a direct link, Mucke noted (Das et al., 2021). 

“The way we put this together is that network dysfunction exists in a vicious cycle with immune dysfunction,” Mucke said. This could play out in various ways in a diseased brain. In some cases, microinfarcts might bring on local overexcitation that triggers an immune response; in others, a TREM2 variant might promote immune dysfunction that leads to excitation. “So this circle keeps churning and leads to synaptic dysfunction and loss,” he said.

Mucke believes both anti-epileptic therapy and tau reduction have the potential to break this cycle. In Dravet mice, lowering tau with antisense oligonucleotides improved survival to nearly wild-type levels.—Madolyn Bowman Rogers

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References

News Citations

  1. Tau Toxicity—Tangle-free But Tied to Inflammation
  2. In Tauopathy, ApoE Destroys Neurons Via Microglia
  3. Microglia Inflammasome Stokes Tau Phosphorylation, Tangles
  4. 11th ICFTD Meeting in Sydney Sorts Out Clinical Subtypes
  5. Curbing Innate Immunity Boosts Synapses, Cognition
  6. Neurons Cave When Astrocytes Heap on the Complements
  7. Paper Alert: Microglia Mediate Synaptic Loss in Early Alzheimer’s Disease
  8. Microglial Master Regulator Tunes AD Risk Gene Expression, Age of Onset
  9. When It Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM?
  10. Most Detailed Look Yet at Activation States of Human Microglia
  11. Hot DAM: Specific Microglia Engulf Plaques
  12. Lowering Tau Tips the Brain's Balance of Excitation/Inhibition

Research Models Citations

  1. rTg(tauP301L)4510

Paper Citations

  1. Onishi T, Matsumoto Y, Hattori M, Obayashi Y, Nakamura K, Yano T, Horiguchi T, Iwashita H. Early-onset cognitive deficits and axonal transport dysfunction in P301S mutant tau transgenic mice. Neurosci Res. 2014 Mar;80:76-85. Epub 2014 Jan 6 PubMed.
  2. Rexach JE, Polioudakis D, Yin A, Swarup V, Chang TS, Nguyen T, Sarkar A, Chen L, Huang J, Lin LC, Seeley W, Trojanowski JQ, Malhotra D, Geschwind DH. Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression. Cell Rep. 2020 Nov 17;33(7):108398. PubMed.
  3. Marciniak E, Leboucher A, Caron E, Ahmed T, Tailleux A, Dumont J, Issad T, Gerhardt E, Pagesy P, Vileno M, Bournonville C, Hamdane M, Bantubungi K, Lancel S, Demeyer D, Eddarkaoui S, Vallez E, Vieau D, Humez S, Faivre E, Grenier-Boley B, Outeiro TF, Staels B, Amouyel P, Balschun D, Buee L, Blum D. Tau deletion promotes brain insulin resistance. J Exp Med. 2017 Aug 7;214(8):2257-2269. Epub 2017 Jun 26 PubMed.
  4. Tai C, Chang CW, Yu GQ, Lopez I, Yu X, Wang X, Guo W, Mucke L. Tau Reduction Prevents Key Features of Autism in Mouse Models. Neuron. 2020 May 6;106(3):421-437.e11. Epub 2020 Mar 2 PubMed.
  5. Das M, Mao W, Shao E, Tamhankar S, Yu GQ, Yu X, Ho K, Wang X, Wang J, Mucke L. Interdependence of neural network dysfunction and microglial alterations in Alzheimer's disease-related models. iScience. 2021 Nov 19;24(11):103245. Epub 2021 Oct 7 PubMed.

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