MARK2 in glial cells suppresses inflammatory responses and mitigates tau toxicity

Neuroinflammation is a pathological hallmark of Alzheimers disease and related neurodegenerative diseases. However, signaling molecules that regulate glial activation status are not fully understood. Microtubule affinity-regulating kinase 2 (MARK2) has been implicated in both immune responses and AD pathology. Here, we report that MARK2 negatively regulates glial immune responses, which protects against neurodegeneration. We found that MARK2 knockdown in the BV2 murine microglial cell line enhanced IL-6 expression in response to LPS. MARK2 knockdown enhanced IL-6 expression induced by TLR7 agonist but not stimulation of RLR pathways and cGAS-STING. In the brains of PS19 tauopathy mice, MARK2 was elevated in homeostatic microglia but reduced in activated microglia. In Drosophila expressing human tau in the retina, expression of AMP downstream of the Toll pathway in the pigment glia enhances degeneration of photoreceptor neurons. Glial knockdown of Par-1, the Drosophila ortholog of MARK2, enhanced Toll-mediated AMP expression and neurodegeneration, whereas overexpression of Par-1 in the pigment glia suppressed them. These results suggest that MARK2/Par-1 in glia negatively regulates Toll pathway-driven inflammation and protects against tau-induced neurodegeneration. These findings provide insight into the molecular underpinnings of glial inflammation in neurodegenerative conditions and highlight MARK2 as a potential therapeutic target for modulating neuroinflammatory responses.