Hyperphosphorylation of Tau promotes its aggregation and formation of neurofibrillary tangles, processes that contribute to neuronal dysfunction and neurodegeneration in Alzheimer disease and related dementias. The upstream mechanisms that lead to dysregulated Tau phosphorylation in pathological contexts remain incompletely defined. Glycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane enzyme localized to the cell surface that cleaves glycosylphosphatidylinositol (GPI) anchors, thereby regulating the membrane localization and activity of a subset of GPI-anchored proteins. The authors investigated whether GDE2 influences Tau phosphorylation in a mouse model of tauopathy and whether such effects vary by brain region.
The study used the PS19 transgenic mouse model expressing mutant human Tau to probe tauopathy-relevant phosphorylation changes. GDE2 was genetically ablated in this background to generate PS19;Gde2KO animals. The authors assessed Tau phosphorylation at multiple epitopes associated with aggregation propensity and anti-aggregation effects across brain regions and ages reported in the source. Additional experiments used primary cortical neurons from PS19;Gde2KO animals and heterologous SH-SY5Y cells to evaluate cell-autonomous effects and requirements for GDE2 catalytic activity.
In the cortex of PS19;Gde2KO mice, GDE2 ablation produced transient delays in phosphorylation at established pro-aggregation sites, specifically Serine/Threonine residues S202/T205, T212, and S396. Concurrently, phosphorylation at the site reported as anti-aggregation, S262, was accelerated. At 6 months of age, cortical Tau showed a marked reduction in phosphorylation at S202/T205 and T212 in PS19;Gde2KO animals compared with PS19 controls. These findings indicate that loss of GDE2 altered the local balance of phosphorylation events in cortex, shifting patterns away from pro-aggregation modification at measured time points.
In the hippocampus, PS19;Gde2KO animals also displayed a delay in phosphorylation at S202/T205, mirroring the cortical delay for that particular epitope. However, by 6 months the hippocampus of PS19;Gde2KO mice showed increased phosphorylation at S262. Thus, while some phosphorylation changes (for example, delayed S202/T205) were shared between cortex and hippocampus, the net outcomes and trajectory by 6 months differed by region, consistent with a region-dependent regulation of Tau phosphorylation by GDE2.
Biochemical assays reported in the source found accompanying changes in kinase activities that correlate with the region-specific Tau phosphorylation patterns. In cortex, activities of AKT and Glycogen Synthase Kinase-3 α/β (GSK3α/β) were decreased in PS19;Gde2KO animals. In contrast, AKT activity was increased in the hippocampus of PS19;Gde2KO mice. The activities of the major Tau-directed phosphatases examined—protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A)—were reported as unchanged across regions. These data support the interpretation that altered local kinase signaling, rather than changes in phosphatase activity, contributes to the observed phosphorylation shifts.
Primary cortical neurons isolated from PS19;Gde2KO animals exhibited reduced Tau phosphorylation at S202/T205 relative to controls, providing evidence that neuronal loss of GDE2 can cell-autonomously influence Tau phosphorylation. This result supports a model in which neuronal GDE2 activity contributes directly to the regulation of local kinase environments and Tau modification within neurons.
In heterologous SH-SY5Y cell experiments, overexpression of wild-type GDE2 increased Tau phosphorylation at S202/T205. A catalytically inactive mutant form of GDE2 failed to increase phosphorylation at this epitope. From these results, the authors infer that the catalytic activity of GDE2 — and by implication cleavage of target GPI-anchored proteins at the cell surface — is required for the observed modulatory effects on Tau phosphorylation.
The findings identify GDE2 as a component of the regulatory network that controls Tau phosphorylation in the context of tauopathy. Because GDE2 influences phosphorylation in a region-specific manner via changes in local kinase activities (notably AKT and GSK3α/β in cortex versus hippocampus), modulation of GDE2 function or downstream GPI-anchored targets could represent a pathway-relevant approach to alter Tau phosphorylation patterns implicated in aggregation. The regional divergence also highlights that interventions aimed at Tau phosphorylation may produce different outcomes across brain regions, an important consideration for translating molecular insights into therapeutic strategies.
This report is presented as a preprint and has not undergone peer review. The source provides experimental observations supporting region-specific regulatory effects of GDE2 on Tau phosphorylation, changes in AKT and GSK3α/β activities, and cell-autonomous neuronal contributions, but detailed mechanistic pathways linking specific GPI-anchored targets to kinase modulation were not reported in the source. Further validation and expanded mechanistic studies will be necessary to confirm causality and to identify the relevant GPI-anchored substrates mediating these effects.