Microglial-neuronal interactions represent a critical nexus in tauopathy pathogenesis, where activated microglia contribute to both tau propagation and neuronal dysfunction. This mechanism bridges innate immunity with neurodegeneration in conditions including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease.
Tauopathies are characterized by the accumulation of pathological tau protein aggregates in neurons and glia. While tau pathology is neuron-centric, mounting evidence demonstrates that microglia—the brain's resident immune cells—play a dual role in disease progression: they attempt to clear pathological tau but inadvertently contribute to its spread and amplify neuroinflammation[1].
In tauopathies, microglia adopt a disease-associated microglia (DAM) phenotype characterized by upregulated genes including TREM2, APOE, CLEC7A, and ITGAX[2]. These cells represent a continuum from homeostatic microglia to a fully activated DAM state:
In PSP and CBD, post-mortem studies demonstrate abundant HLA-DR+ microglia in regions with high tau pathology, particularly in the basal ganglia, brainstem, and cortical areas[3].
Microglial activation correlates with tau burden in specific brain regions:
Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical receptor governing microglial responses to tau pathology[4]:
TREM2 activation → DAP12 phosphorylation → SYK activation →
PI3K/Akt pathway → Survival, proliferation, phagocytosis
Genetic variants in TREM2 (including the R47H variant) increase risk for both Alzheimer's disease and certain tauopathies[5]. These variants impair microglial ability to:
| Receptor | Ligand | Role in Tauopathy |
|---|---|---|
| TLR2/TLR4 | Tau aggregates | Pro-inflammatory cytokine induction |
| CD33 | Sialic acid | Phagocytic regulation |
| CX3CR1 | Fractalkine (CX3CL1) | Microglial-neuronal communication |
| SIRPα | CD47 | "Don't eat me" signaling |
Microglia can internalize extracellular tau through multiple pathways[6]:
Once internalized, tau can be transferred to neurons through:
Microglial-processed tau retains seeding capability, meaning ingested tau can templated aggregation of endogenous neuronal tau[7]. This creates a vicious cycle where microglia inadvertently propagate pathology.
Activated microglia in tauopathies produce a characteristic cytokine profile[8]:
| Cytokine | Source | Effects |
|---|---|---|
| IL-1β | NLRP3 inflammasome | Neuronal tau phosphorylation |
| IL-6 | Multiple cell types | Synaptic dysfunction |
| TNF-α | Activated microglia | Neuronal apoptosis |
| IL-18 | NLRP3 inflammasome | Pro-inflammatory amplification |
Microglial-derived factors affect neuronal health through:
TREM2 agonists are being developed to enhance microglial function[9]:
NLRP3 inhibitors (e.g., MCC950) show promise in preclinical models[10]:
Minocycline and other broad-spectrum anti-inflammatory agents have been tested in clinical trials with mixed results.
Balancing microglial phagocytosis is critical:
Colony-stimulating factor 1 receptor (CSF1R) blockade can reduce microglial proliferation and activation[11]. However, complete depletion may compromise brain immune surveillance.
Recent advances in microglial-neuronal tauopathies research:
Leyns, C. E. G., & Holtzman, D. M. Glial contributions to neurodegeneration in tauopathies. Molecular Neurodegeneration. 2017. ↩︎
Keren-Shaul, H., et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017. ↩︎
Forman, M. S., et al. Activated microglia in motor cortex of PSP and FTD. Acta Neuropathologica. 2005. ↩︎
Wang, Y., et al. TREM2 mediates microglial phagocytosis of amyloid plaques. Cell. 2015. ↩︎
Ruiz, A., et al. TREM2 and neurodegeneration: risk variants and function. Current Alzheimer Research. 2014. ↩︎
Bolós, M., et al. Novel insights into the role of microglia in tauopathies. Cellular and Molecular Neurobiology. 2016. ↩︎
Hopp, S. C., et al. The role of microglia in processing and spreading of tau pathology. Neurobiology of Disease. 2018. ↩︎
Heneka, M. T., et al. Neuroinflammation in Alzheimer's disease. The Lancet Neurology. 2015. ↩︎
Schlepckow, K., et al. TREM2 as a therapeutic target in Alzheimer's disease. EMBO Molecular Medicine. 2020. ↩︎
Dempsey, C., et al. NLRP3 inflammasome activation in Alzheimer's disease. Brain. 2017. ↩︎
Olmos-Alonso, A., et al. CSF1R inhibition reduces microglial proliferation. Brain. 2016. ↩︎