# Investigating physiological pathways modulating tau homeostasis: potential implications for Alzheimer's Disease and Related Dementia

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary:
Cytoskeletal abnormalities are prominent features in a wide variety of neurodegenerative diseases and have
been attributed to induce neuronal death. In Alzheimer’s disease (AD) and AD-related dementias such as
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD), microtubule-associated protein tau
(tau) is hyperphosphorylated and aggregates into neurofibrillary tangles (NFTs), which contributes to
mitochondrial dysfunction, disrupted autophagy, and neuronal death. Despite the critical role of tau abnormalities
in neurodegenerative diseases like AD and ALS-FTD, how this dysregulation arises is not fully understood. Our
group has found a signaling pathway that when disrupted, leads to changes in tau post-translational
modifications that are associated with disease. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5)
is the only known protein in vertebrates that acts at the cell surface in neurons to cleave the
glycosylphosphatidylinositol (GPI)-anchor that tethers a subclass of proteins to the membrane. GDE2 has been
shown to aberrantly accumulate intracellularly in neurons of patients with AD and ALS. Consistent with GDE2
dysfunction in disease, biochemical studies in postmortem AD brain confirm impaired GPI-anchored protein
processing, while proteomic studies of patient cerebrospinal fluid (CSF) reflect a decrease in neuronally
expressed GPI-anchored proteins in the CSF of ALS patients. GDE2 deletion in the APP/PS1 mouse model of
amyloidosis leads to an increase in tau phosphorylation, and preliminary studies in primary cultured neurons
from the PS19 humanized tauopathy mouse model show that loss of GDE2 results in increased tau levels and
phosphorylation. These observations suggest that GDE2 is required for regulating the dynamics of tau
phosphorylation. The overarching hypothesis to be tested in this proposal is that GDE2 is an important
regulator of tau post-translational modifications and that GDE2 inactivation contributes to tau
abnormalities in disease. In Aim 1, I will utilize the PS19 model to examine how the loss of GDE2 affects the
onset and progression of neurodegeneration in the context of tau modifications and aggregation in vivo and in
vitro. In Aim 2, I will explore the pathway through which GDE2 modulates tau post-translational modifications
through structure-function analysis of GDE2 and by taking a candidate-based approach that focuses on select
GPI-anchored substrates associated with AD and ADRDs. In Aim 3, I will determine the relevance of GDE2 to
tau pathology in AD postmortem brain. Together, the outcomes of my project will provide insight into pathways
relevant to tau pathology observed in AD and ADRDs and could provide novel targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10899143
- **Project number:** 1F31AG087599-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Consuelo Jimenez-Ornelas
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899143

## Citation

> US National Institutes of Health, RePORTER application 10899143, Investigating physiological pathways modulating tau homeostasis: potential implications for Alzheimer's Disease and Related Dementia (1F31AG087599-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10899143. Licensed CC0.

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