Region-dependent regulation of Tau phosphorylation by Glycerophosphodiester Phosphodiesterase 2 in a mouse model of tauopathy

Hyperphosphorylation of Tau promotes its aggregation and neurofibrillary tangle (NFT) formation, contributing to neuronal dysfunction and neurodegeneration in diseases such as Alzheimer's Disease (AD) and AD-related dementias (ADRDs). However, the mechanisms underlying dysregulated Tau phosphorylation under pathological contexts remain unclear. Glycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers a subclass of proteins to the membrane. Here, we show that in the PS19 tauopathy mouse model, GDE2 disruption modulates Tau phosphorylation by transiently decreasing Tau's propensity for aggregation through region-specific regulation of local kinase environments. In the cortex, GDE2 ablation in 6-month-old PS19 male mice (PS19;Gde2KO) reduces Tau phosphorylation at Serine (S)202/Threonine (T)205, T212, and S396 but increases S262 phosphorylation in the hippocampus of 6-month-old PS19;Gde2KO male and female mice. Consistent with these changes, in males, Glycogen Synthase Kinase-3 / {beta} (GSK3 / {beta}) activity is decreased in the cortex, while AKT activity is increased in both males and females in the hippocampus, with no changes in protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activity. Primary cortical neurons from PS19;Gde2KO animals showed reduced Tau phosphorylation at S202/T205, implying cell-autonomous roles for neuronal GDE2 in this process. GDE2 overexpression in heterologous SH-SY5Y cells increased Tau phosphorylation at S202/T205, while a catalytically inactive form of GDE2 did not, suggesting that GDE2 regulation of target GPI-anchored protein surface activity is required to modulate Tau phosphorylation. Taken together, our study identifies GDE2 as a component of the complex regulatory network that controls Tau phosphorylation in the context of tauopathy and provides insight into putative pathways relevant to Tau pathologies observed in disease.