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

In the PS19 tauopathy mouse model, disrupting Glycerophosphodiester phosphodiesterase 2 (GDE2) shifts Tau phosphorylation in a region-specific way, reducing S202/T205, T212, and S396 while increasing S262.

• Why it matters: Tau hyperphosphorylation drives aggregation and neurofibrillary tangle formation, but how pathological contexts dysregulate phosphorylation across brain regions is unclear.
• What they did: The authors compared 6-month-old PS19;Gde2KO mice with controls, measuring Tau phosphorylation in cortex versus hippocampus and kinase/phosphatase activities; they also tested cell-autonomous effects in primary cortical neurons and GDE2 overexpression in SH-SY5Y cells.
• The result: In males, GSK3/β activity decreased in cortex and AKT activity increased in hippocampus without PP1/PP2A changes, and neuronal GDE2 loss reduced Tau phosphorylation at S202/T205, while active (but not catalytically inactive) GDE2 increased S202/T205 in SH-SY5Y cells.

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