Just Like Viruses, Tau Can Unleash Interferons
Known as first responders to viral infection, Type I interferons may also play a part—for better or worse—in neurodegenerative disease. At AD/PD 2022, held March 15-20 online and in Barcelona, Spain, researchers reported that not only viruses, but also aggregates of tau can set the interferon cascade in motion. Possibly by damaging mitochondria enough to let their DNA escape, tau aggregates triggered a cytosolic DNA sensor called cyclic GMP-AMP synthase. This, in turn, set off the interferon response, leading to destruction of synapses. Deleting or blocking cGAS spared synapses and memory in mouse models of tauopathy, despite having no effect on tau tangles. Scientists in Barcelona also reported that interferon signaling proteins were elevated in the cerebrospinal fluid of people who tested positive for amyloid plaques and/or tau tangles. The findings cast interferon as a bad actor responding to both pathologies, and may point to therapeutic targets that prevent the neuronal damage caused by this inflammatory response.
- Tau fibrils trigger activation of cGAS, a cytosolic DNA sensor that switches on interferon.
- Leaked mitochondrial DNA may set off the alarm.
- A cGAS inhibitor spared synapses and memory in tauopathy mice.
- In people, interferon cascades associate with Aβ plaques and tau tangles.
Innate immune mechanisms that have evolved to thwart invading microbes are increasingly recognized as players in neurodegenerative disease. Type I interferons are typically activated by cellular sensors that detect viral RNA or DNA, but recent studies suggest that in the face of Aβ or tau pathology, some microglia turn on a similar interferon cascade (Tan et al., 2018; Dec 2020 news; and Mar 2022 conference news). If not viruses, then what could be setting this off? Curiously, one study found that misplaced or damaged endogenous DNA—such as that found mingling within Aβ plaques—can do so, leading to dead synapses and faster cognitive decline (Roy et al., 2020).
How might tau pathology rev this interferon cascade? Using RNA-Seq, Sadaf Amin, a postdoc in Li Gan’s lab at Weill Cornell Medical College in New York, found that multiple interferon-stimulated genes ramped up in the brains of P301S tauopathy mice, and that cGAS could be the upstream trigger. This sensor detects foreign viral DNA as well as endogenous mitochondrial and nuclear DNA that have leaked into the cytosol. Upon detecting these misplaced nucleic acids, cGAS activates STING, which leads to recruitment and phosphorylation of TBK-1.This kinase phosphorylates the transcription factor IRF3, which then dimerizes and heads into the nucleus, where it sets off the transcription of type I interferon genes (for review, Hopfner and Hornung, 2020).
To find the source of the interferon in the mice, Amin first turned to the most likely suspects, the brain's immune cells. In Barcelona, Amin reported that when they treated cultured microglia with synthetic tau fibrils, levels of p-TBK1, IFN-β, and interferon-stimulated genes all increased, suggesting the cGAS-interferon pathway had been switched on. But how? The scientists spotted tau fibrils congregating in some mitochondria, and found that depleting cells of mitochondrial DNA dampened the interferon response. Knocking out cGAS almost completely abolished the response as well. Together, the findings suggested that tau fibrils may trigger leakage of mitochondrial DNA, which trips off cGAS and the interferon cascade.
How might tau aggregates leak mitochondrial DNA into the cytosol? This is an open question, but Amin spotted tau aggregates within the organelles. A recent study from Gan’s lab found that tau interacts with multiple mitochondrial proteins in neurons, suggesting that the microtubule-binding protein may have a proclivity for this organelle (Jan 2022 news). Another recent study found tau aggregates cavorting with a mitochondrial protein within synapses, ultimately leading the organelles to break in two (Mar 2022 conference news). It is also possible that the phenomenon extends beyond tau, since others have watched Aβ damage mitochondria, and TDP-43 was recently reported to enter these little factories as well, triggering the release of mtDNA and activating the cGAS–STING pathway (Yu et al., 2020).
Cooking with cGAS
To investigate the role of cGAS in tauopathy in vivo, the researchers generated cGAS homo- and heterozygous knockouts on a non-transgenic or P301S background. Using single-nuclei RNA sequencing, Amin found upregulation of multiple interferon-stimulated genes in microglia from P301S mice compared to controls. Knocking out one or two copies of cGAS suppressed this. Furthermore, ditching cGAS prevented synaptic loss, synaptic dysfunction, and spatial memory deficits in the tauopathy mice, although it did not lighten their load of neurofibrillary tangles.
Finally, a brain-permeable cGAS inhibitor, called TDI-8570, bestowed similar benefits. Added to mouse kibble for three months, it reduced synapse loss in P301S mice and sharpened their recognition of new objects. The inhibitor had no effect on the memory of non-transgenic mice.
Amin found evidence that the cGAS-STING pathway was cranked up in humans, as well. People with AD had more phospho-TBK1 in their brains than did controls. The findings mesh with previous transcriptomic studies that have identified subsets of microglia with ongoing interferon responses in the AD brain (Dec 2020 news).
Mapping Inflammation to PET Signals
While Amin’s study focused on tau, a jumble of different aggregated proteins typically haunt the brains of people with AD, and each may invoke its own brand of inflammation. Which pathways are triggered by plaques and tangles, and how do they relate to progression of disease? At AD/PD, Bruna Bellaver, from the lab of Tharick Pascoal at the University of Pittsburgh in Philadelphia, presented findings from a study that dissected the inflammatory pathways associated with plaques and tangles in members of the TRIAD cohort at McGill University in Montreal.
Bellaver and colleagues measured CSF levels of 92 inflammatory proteins among 35 cognitively normal and 25 cognitively impaired participants. They plugged these 92 proteins into a so-called STRING database, which integrates data from multiple studies to group proteins based on their involvement in similar signaling pathways. STRING identified six clusters within the CSF marker dataset, and each could be scored based on the CSF levels of each member protein. Comparing the scores to each participant’s PET scans, Bellaver found that two clusters associated with both plaques and tangles, while one cluster associated only with plaques and another only with tangles. Interestingly, none of the clusters correlated with cognitive status.
Essentially, Bellaver found that clusters relating to JAK-STAT signaling and glial cell neurotrophic receptor binding correlated with Aβ plaques as well as tau tangles. JAK-STAT signaling is triggered when interferon binds to its receptor, suggesting that the interferon response is associated with both amyloid and tau accumulation. The cluster that correlated only with plaques also reflects interferon responses, this time stimulation of interferon-gamma, a type II interferon. Lastly, a TNF-α signaling cluster only correlated with tangles. In all, the findings reveal distinct inflammatory signatures of Aβ plaques and tau tangles in the human brain, with substantial overlap between the two. Notably, Type I interferon signaling emerged as a commonality between the two signatures.
The data can’t predict whether the different inflammatory pathways were cause or consequence of each type of pathology. They do, however, suggest that inflammation is an early part of the disease process and heats up well before cognitive symptoms surface, Pascoal said. He noted that numerous other genetic, health, and environmental factors also contribute to inflammatory pathways active in the brain. Teasing apart the inflammatory signatures invoked by these different contributors will help scientists understand which ones to target, and when.—Jessica Shugart
- Microglia in Tauopathy: Not Just Homeostatic Versus DAM
- Tau Triggers Neuroinflammation, But Mechanisms Vary by Disease
- Survey of Tau Partners Highlights Synaptic, Mitochondrial Roles
- At Tau2022: Unknown Functions Emerge for Tau, LRRK2
- Most Detailed Look Yet at Activation States of Human Microglia
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- Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020 Sep;21(9):501-521. Epub 2020 May 18 PubMed.
- Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RR, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020 Oct 29;183(3):636-649.e18. Epub 2020 Oct 7 PubMed.
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