The neuroimmune interface represents the critical bidirectional communication network between neurons and immune cells—primarily microglia and astrocytes—in the central nervous system. In 4R-tauopathies like corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), this communication network becomes profoundly dysregulated, contributing to disease progression through chronic neuroinflammation, synaptic loss, and neuronal dysfunction[@mangold2021].
Pathological alterations in CBS/PSP:
Microglial activation: Prominent in affected brain regions (basal ganglia, brainstem, frontal cortex)
Astrocyte reactivity: Tufted astrocytes are a hallmark of PSP
Complement activation: C1q and C3 mediate excessive synaptic pruning
Cytokine elevation: TNF-α, IL-1β, IL-6 elevated in CSF
TREM2 dysfunction: Impaired phagocytic clearance of tau aggregates
Therapeutic modulation of neuroimmune communication offers a complementary approach to direct anti-tau therapies, potentially enhancing clearance mechanisms while reducing neurotoxic inflammation.
147.2 Glial-Neuronal Crosstalk Pathways
CX3CL1/CX3CR1 Signaling Axis
The fractalkine pathway provides the primary inhibitory communication channel from neurons to microglia:
[Mangold CA, Wold LE. The neuroimmune interface: cytokine networks in brain aging. Ageing Res Rev. 2021](https://pubmed.ncbi.nlm.nih.gov/33276197/)
[Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017](https://pubmed.ncbi.nlm.nih.gov/28636959/)
[Deczkowska A, Weiner A, Amit I. The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell. 2020](https://pubmed.ncbi.nlm.nih.gov/32521223/)
[Heneka MT, McManus RM, Latz E. NLRP3 inflammasome in spatial and temporal memory. Nat Rev Neurosci. 2019](https://pubmed.ncbi.nlm.nih.gov/31363276/)
[Griffiths DR, Dagher M. Astrocyte-microglia cross-talk in neurodegenerative disease. Nat Rev Neurol. 2023](https://pubmed.ncbi.nlm.nih.gov/36658318/)
References
[Mangold CA, Wold LE et al, Mangold CA, Wold LE. The neuroimmune interface: cytokine networks in brain aging. Ageing Res Rev. 2021;65:101147 (2021)](https://doi.org/10.1016/j.arr.2020.101147)
[Liddelow SA, Barres BA et al, Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46(6):957-967 (2017)](https://doi.org/10.1016/j.immuni.2017.06.006)
[Deczkowska A, Weiner A, Amit I et al, Deczkowska A, Weiner A, Amit I. The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell. 2020;181(6):1207-1217 (2020)](https://doi.org/10.1016/j.cell.2020.05.014)
[Heneka MT, McManus RM, Latz E et al, Heneka MT, McManus RM, Latz E. NLRP3 inflammasome in spatial and temporal memory. Nat Rev Neurosci. 2019;20(9):521-534 (2019)](https://doi.org/10.1038/s41583-019-0181-x)
[Griffiths DR, Dagher M et al, Griffiths DR, Dagher M. Astrocyte-microglia cross-talk in neurodegenerative disease. Nat Rev Neurol. 2023;19(3):139-151 (2023)](https://doi.org/10.1038/s41582-023-00685-5)