---
title: "Region-specific regulation of Tau phosphorylation by GDE2 in a PS19 mouse model"
id: "biorxiv-11-region-dependent-regulatioin-of-tau-phosphorylation-in-a-mouse-model-of"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-11-region-dependent-regulatioin-of-tau-phosphorylation-in-a-mouse-model-of"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.14.751492v1?rss=1"
published_at: "2026-09-21T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Region-specific regulation of Tau phosphorylation by GDE2 in a PS19 mouse model
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-11-region-dependent-regulatioin-of-tau-phosphorylation-in-a-mouse-model-of
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.14.751492v1?rss=1)
- **Published At:** 2026-09-21T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Hyperphosphorylation of **Tau** drives aggregation and neurofibrillary tangle formation in Alzheimer disease and related dementias; mechanisms that dysregulate Tau phosphorylation in disease are incompletely understood. - Glycerophosphodiester phosphodiesterase 2 (**GDE2**) is a six-transmembrane enzyme that cleaves GPI anchors at the cell surface, modulating the activity of a subset of membrane-tethered proteins. - Using the PS19 tauopathy mouse model, genetic ablation of **GDE2** (PS19;Gde2KO) produced **region-dependent** changes in Tau phosphorylation patterns, with distinct effects in cortex versus hippocampus. - In cortex, GDE2 loss transiently delayed phosphorylation at pro-aggregation epitopes (S202/T205, T212, S396) and increased phosphorylation at the anti-aggregation site **S262**, with marked reduction in S202/T205 and T212 phosphorylation observed at 6 months. - In hippocampus, S202/T205 phosphorylation was similarly delayed, but PS19;Gde2KO animals showed increased phosphorylation at **S262** by 6 months, indicating divergent local outcomes. - Kinase activity changes accompanied the phosphorylation shifts: cortical reductions in **AKT** and **GSK3α/β** activities contrasted with increased AKT activity in the hippocampus; activities of PP1 and PP2A phosphatases were unchanged. - Primary cortical neurons from PS19;Gde2KO mice showed reduced S202/T205 phosphorylation, supporting a cell-autonomous neuronal role for GDE2 in modulating Tau phosphorylation. - Overexpression of wild-type GDE2 in SH-SY5Y cells increased Tau phosphorylation at S202/T205, whereas a catalytically inactive GDE2 mutant did not, implicating GDE2 catalytic activity and GPI-anchor cleavage in the regulatory mechanism. - Collectively, the data identify **GDE2** as a component of the regulatory network controlling Tau phosphorylation in tauopathy and suggest that modulation of GPI-anchored protein activity can influence local kinase environments and Tau phosphorylation in a region-specific manner. - This report is a preprint and has not undergone peer review; further validation and mechanistic detail beyond what is reported here were not provided in the source.
## Clinical Analysis & Structured Key Points
Region-dependent regulatioin of Tau phosphorylation in a mouse model of tauopathy | bioRxiv Skip to main content New Results Region-dependent regulatioin of Tau phosphorylation in a mouse model of tauopathy Consuelo Jimenez-Ornelas , Shanthini Sockanathan doi: https://doi.org/10.64898/2026.09.14.751492 Consuelo Jimenez-Ornelas Johns Hopkins University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shanthini Sockanathan Johns Hopkins University Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: ssockan1{at}jhmi.edu Abstract Info/History Metrics Supplementary material Preview PDF 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, 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 α / β (GSK3 α / β) 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. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared National Institute of Aging , 1F31AG087599-01 National Institute of Health , T32NS091018 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 21, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Region-dependent regulatioin of Tau phosphorylation in a mouse model of tauopathy Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Region-dependent regulatioin of Tau phosphorylation in a mouse model of tauopathy Consuelo Jimenez-Ornelas , Shanthini Sockanathan bioRxiv 2026.09.14.751492; doi: https://doi.org/10.64898/2026.09.14.751492 Share This Article: Copy Citation Tools Region-dependent regulatioin of Tau phosphorylation in a mouse model of tauopathy Consuelo Jimenez-Ornelas , Shanthini Sockanathan bioRxiv 2026.09.14.751492; doi: https://doi.org/10.64898/2026.09.14.751492 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8015) Biochemistry (18744) Bioengineering (14890) Bioinformatics (44453) Biophysics (22610) Cancer Biology (19728) Cell Biology (26906) Clinical Trials (138) Developmental Biology (13970) Ecology (21008) Epidemiology (2067) Evolutionary Biology (25457) Genetics (16171) Genomics (23513) Immunology (18717) Microbiology (42520) Molecular Biology (18064) Neuroscience (93479) Paleontology (700) Pathology (2982) Pharmacology and Toxicology (5100) Physiology (8116) Plant Biology (16000) Scientific Communication and Education (2095) Synthetic Biology (4560) Systems Biology (10237) Zoology (2391)
## Related Clinical Research

- [CA1 Place Code Refines and Shifts Retrospectively During Food-Carrying Decisions](https://medichelpline.com/clinical-feed/biorxiv-0-refinement-and-retrospective-shift-of-the-ca1-place-code-during-food-carrying.md)
- [Physiological variability in Alzheimer's biomarkers and the mechanistic basis for ratio normalizat](https://medichelpline.com/clinical-feed/medrxiv-7-physiological-variability-in-key-alzheimer-s-biomarkers-in-amyloid-positive.md)
- [MALDI-TOF imaging reveals sex- and age-dependent shifts in brain lactate metabolism in an Alzheime](https://medichelpline.com/clinical-feed/biorxiv-17-maldi-tof-imaging-mass-spectrometry-demonstrates-sex-and-age-dependent-spatial.md)
- [Orexin agonist ALKS 7290 shows ADHD symptom improvement in early Phase 1 trial](https://medichelpline.com/clinical-feed/stat-news-0-stat-alkermes-orexin-agonist-shows-potential-to-treat-adhd-in-early-stage-trial.md)
- [Atypical Alzheimer disease: a multi-axis framework to define clinical and biological heterogeneity](https://medichelpline.com/clinical-feed/nature-reviews-neurology-0-atypical-alzheimer-disease-a-multi-axis-framework-toward-defining-heterogeneity.md)

## Navigation
- [← Back to Neurology Feed](https://medichelpline.com/clinical-feed/neurology.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.