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, decreasing Tau's propensity for aggregation by regulating local kinase environments in a region-specific manner. In the cortex, GDE2 ablation in PS19 mice (PS19;Gde2KO) transiently delays Tau phosphorylation at pro-aggregation sites (Serine (S)202/Threonine (T)205, T212, and S396) and accelerates phosphorylation at the anti-aggregation site S262, with a marked reduction in S202/T205 and T212 phosphorylation at 6 months. While Tau phosphorylation at S202/T205 is similarly delayed in the hippocampus, PS19;Gde2KO animals show increased phosphorylation at S262 at 6 months. Consistent with these changes, AKT and Glycogen Synthase Kinase-3 / {beta} (GSK3 / {beta}) activities are decreased in the cortex, while AKT activity is increased 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.
Jimenez-Ornelas, C., Sockanathan, S.
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