Microglia have been firmly linked to amyloid plaques, but scientists are only beginning to examine their relationship to tau tangles. In the November 20 Nature, Michael Heneka and colleagues at the German Center for Neurodegenerative Diseases in Bonn suggest that microglial inflammation incites tau toxicity, too. Activated microglia secrete proinflammatory cytokines that signal neurons to ramp up tau phosphorylation, the authors found. Keeping microglia quiescent by deleting their NLRP3 inflammasome blocked tangle formation in a tauopathy mouse model. Loss of inflammasome also prevented tau aggregation in response to injected Aβ.
- Activated microglia release cytokines that trigger tau phosphorylation in neurons.
- Ablating microglial NLRP3 inflammasome curbed tangles in tau mice.
- It also prevented tangles caused by injected Aβ seeds.
The findings add to the evidence that microglia propel Alzheimer’s pathology, and hint that they could link plaques and tangles in the amyloid cascade. “Aβ activates the innate immune system, and that drives tau phosphorylation,” Heneka said.
“These are exciting and dramatic results,” Marc Diamond, University of Texas Southwestern Medical Center in Dallas, told Alzforum. “It would be extremely interesting to see if similar effects result from inflammasome inhibitors, and whether those effects hold up across different mouse models of tauopathy and other proteinopathies.”
Previously, Heneka proposed a role for microglia in amyloid plaque seeding, proposing that activated microglia secrete protein complexes called ASC specks that accelerate Aβ deposition (Dec 2017 news). Other groups also blame microglia for amyloidosis, reporting an almost complete absence of parenchymal plaques when they are missing (Mar 2018 news; Sep 2019 news).
Links between microglia and tau pathology have been more tenuous. Virginia Lee’s group at the University of Pennsylvania, Philadelphia, implicated microglial activation in tangle formation in a tauopathy model (Feb 2007 news). Kiran Bhaskar’s at the University of New Mexico, Albuquerque, implicated microgliosis in tau pathology and spreading (Oct 2010 news; Maphis et al., 2015). Recently, David Holtzman’s at Washington University in St. Louis tied microglial ApoE to tangle formation and neurodegeneration (Oct 2019 news). Exactly how microglia promote tau pathology remained unclear, however.
To investigate, Heneka and colleagues turned to Tau22 mice, which express human tau carrying the P301S and G272V mutations. These mice develop tangles and gliosis at 3 months, memory problems at 6, and widespread pathology by 9 months of age. First author Christina Ising found that proinflammatory signaling in the cortex rose at 3 months. By 8 months, some microglia had assumed an activated, amoeboid shape. These cells had turned on the NLRP3 inflammasome, as seen by the release of ASC specks and the proinflammatory cytokine IL-1β, and they were adjacent to tau tangles.
Did this make tau pathology worse? Yes, Ising found. When the authors bred Tau22 mice with NLRP3 knockouts, the crosses accumulated only half as much hyperphosphorylated and aggregated tau by 11 months as the Tau22 mice. Phospho-tau was detected with antibody AT8, which recognizes phosphorylations at serine 202 and threonine 205. Mice without the inflammasome performed as well as wild-types in the Morris water maze.
The researchers used primary cell preparations to investigate how this might happen. Conditioned media from mouse microglia boosted phosphorylation at tau serines 396 and Ser404 in mouse neurons, pointing to soluble factors. Blocking the IL-1 receptor on neurons, or its downstream effectors, prevented p-tau. This suggested IL-1β might be a culprit. This cytokine appears to accelerate tau phosphorylation by affecting neuronal enzymes. In the hippocampi of Tau22 mouse lacking NLRP3, GSK-3β and CaMKII-α kinases were less active while the phosphatase PP2A was more active; together, this dialed down tau phosphorylation.
But what activates NLRP3 in the first place? In Tau22 mice, it might be tau itself, the authors report. In primary microglial cultures from these mice, 2 μM exogenous monomeric and oligomeric tau, but not fibrils, revved up NLRP3. Both wild-type and mutant human tau had this effect. The findings suggest a feedback loop, where tau accumulation kindles inflammation, which then fuels tau pathology.
What about AD? In this disease, Aβ likely kicks off the cascade that leads to microgliosis and tangles, conclude the authors. They injected brain homogenate from APP/PS1 mice into the hippocampi of 3-month-old Tau22 animals. Five months later, they had accumulated twice as much hyperphosphorylated tau in their hippocampi as Tau22 controls. NLRP3 knockouts were protected, however, with APP/PS1 homogenate having no effect on tau.
These data pry open the mechanistic link between plaques and tangles, Heneka believes. Researchers have long known that aggregated Aβ triggers tangle formation in mice (Aug 2001 news; Bolmont et al., 2007). Human imaging validated the mouse data, showing that the spread of plaques through the brain opens the floodgates for tangles to invade the cortex from the medial temporal lobe (Aug 2016 news; Jun 2017 news; May 2019 news). But the exact nexus between the two pathologies remains mysterious.
Now research is homing in on microglia as the missing link. A statistical analysis of human postmortem cortex found that microglial activation follows plaques but precedes tangles in the AD brain (Feb 2019 news). Genetics suggest that the key factor in whether someone develops Alzheimer’s is how their microglia respond to amyloid (Apr 2019 conference news; Aug 2019 news; Nov 2019 news). The present data strengthen the evidence for microglia being a linchpin of the cascade, after amyloid but prior to tau pathology and cognitive decline.
Heneka thinks of Alzheimer’s as a relay race, where a succession of different pathologies propel the disease. Amyloidosis is the first runner. Once it has passed the baton to microglia, targeting amyloid does no good, he said. Likewise, once microglia have initiated tangle formation, the window for dampening inflammation may have passed. This implies therapeutic interventions will have to be tailored to the disease stage. Complicating matters, different brain regions may be at different stages in this cascade at any given point in time, Heneka noted. And different microglia may be at different stages of activation, as well. A current analysis of human brain biopsy samples suggests a spectrum of microglial activation states that depend on a person’s age, location in the brain, and the type of trauma experienced (Nov 2019 news).
To try to figure all this out, Heneka helps run the DELCODE study at DZNE, which follows about 1,000 patients at different stages of AD with cognitive testing, fluid biomarkers, structural MRI, and PET. The goal is to link inflammatory markers in cerebrospinal fluid and blood to neurodegeneration in specific brain regions. “We want to build an inflammatory map of the entire disease trajectory in order to know which brain regions to treat at what stage of disease,” Heneka explained.
One possible treatment would be to inhibit the NLRP3 inflammasome. There are various compounds that do this, and Heneka noted that biotech and pharma companies are developing brain-penetrant inhibitors (Sep 2017 news; Nov 2019 news). Earlier this year, Novartis acquired IFM Tre, a subsidiary of IFM Therapeutics that has a systemic NLRP3 inhibitor in Phase 1 trials, and a brain-penetrant version in preclinical studies.
Microglial inflammation may help propagate other pathologies, too. Seung-Jae Lee at Seoul National University College of Medicine reported earlier this year that α-synuclein oligomers injected into mouse brain did not spread by templated misfolding alone. Instead, these oligomers stimulated microgliosis, which then released proinflammatory cytokines that triggered α-synuclein aggregation in nearby neurons (May 2019 conference news).—Madolyn Bowman Rogers
- Do Microglia Spread Aβ Plaques?
- Wiping Out Microglia Prevents Neuritic Plaques
- Are Microglia Plaque Factories?
- Tau Toxicity—Tangle-free But Tied to Inflammation
- Paper Alert: Fractalkine Receptor Hits Aβ, Tau, in Opposite Ways
- In Tauopathy, ApoE Destroys Neurons Via Microglia
- Finally United? Aβ Found to Influence Tangle Formation
- Brain Imaging Suggests Aβ Unleashes the Deadly Side of Tau
- Analysis of PET Scans Suggests Link Between Amyloid and Tau
- Longitudinal Tau-PET Links Aβ to Subsequent Rise in Cortical Tau
- In Pathology Cascade, Microglia Rev Up After Plaques but Before Tangles
- Expression, Expression, Expression—Time to Get on Board with eQTLs
- AD Genetic Risk Tied to Changes in Microglial Gene Expression
- Cell-Specific Enhancer Atlas Centers AD Risk in Microglia. Again.
- The Human Brain Hosts a Menagerie of Microglia
- New AD Target: Silencing the NLRP3 Inflammasome with Boron?
- Acetaminophen Derivative Tempers Microglia, Spurs Plaque Clearance
- Do Immune Cells Promote the Spread of α-Synuclein Pathology?
Research Models Citations
- Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015 Jun;138(Pt 6):1738-55. Epub 2015 Mar 31 PubMed.
- Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, Jucker M. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am J Pathol. 2007 Dec;171(6):2012-20. PubMed.
- ApoE: Common Microglial Culprit in Aging, Alzheimer’s, and Tauopathy?
- Tau PET Aligns Spread of Pathology with Alzheimer’s Staging
- Imaging Clinches Causal Connections between Aβ, Tau, Circuitry, and Cognition
- Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse
- Parsing How Alzheimer’s Genetic Risk Works Through Microglia
- Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, Griep A, Santarelli F, Brosseron F, Opitz S, Stunden J, Merten M, Kayed R, Golenbock DT, Blum D, Latz E, Buée L, Heneka MT. NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov;575(7784):669-673. Epub 2019 Nov 20 PubMed.