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

Abstract

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.