# Targeting emerging P2RX7 signaling pathways in animal models of Alzheimer's disease

> **NIH NIH R01** · MAYO CLINIC  JACKSONVILLE · 2023 · $391,250

## Abstract

Neurofibrillary tangles, composed of intracellular aggregates of hyperphosphorylated tau protein are by far the
most correlated pathology with clinical symptoms of Alzheimer disease (AD). Emerging evidence suggests
that extracellular vesicles (EVs), such as exosomes and microvesicles, transfer pathological tau protein
between cells as vehicles, and propagate tau pathology in different brain regions. It is urgently important to
find the molecular basis of brain-derived EV, which critically regulates the transport and uptake of pathogenic
tau protein between neuronal cells and aggregation of tau protein in recipient neurons.
 The purpose of the current application is to delineate the effect of P2RX7, a purinergic receptor, on EV-
mediated tau propagation. Our preliminary data have shown that suppressing microglial EV secretion by GSK
1482160 compound, a specific inhibitor of the P2RX7, dramatically reduces tau aggregation in CA1 and CA3
pyramidal neuronal cells and dentate granular cells with P301S tauopathy animal model. Interestingly this
coalesces with reduction of exosome-specific ‘endosomal sorting complexes required for transport’ (ESCRT)
EV marker, TSG101, in the same hippocampal regions, suggesting the possible EV trafficking from microglia
to hippocampal neurons, which may transfer and seeds misfolded tau and accelerate protein aggregation in
receiving neurons. Thus, those data indicate the regulatory mechanism by P2RX7 on EV mediated tau
propagation and posit the therapeutic potential of the P2RX7 inhibitor for AD or other tauopathy. We
hypothesize that P2RX7 critically regulates the transfer of EVs between microglia and neurons in the
hippocampal neurons, thereby facilitate spreading misfolded tau. We will validate the effect of
GSK1482160 on tau propagation by recapitulating those findings using P2rx7 deletion in P301S tau mice and
adeno-associated virus (AAV)-based tau propagation mouse model.
 In Aim 1, we will determine the effect of systemic deletion of P2rx7 in P301S mouse. The distribution of
EV markers and tau pathology in the hippocampal regions will be evaluated and compared with the findings
from GSK1482160-administered P301S mice. In Aim 2, we will determine the effect of P2RX7 on secretion
and transfer of EV and EV-associated tau and its aggregation potency in vitro. This will determine which cell
type is particularly responsible for P2RX7 regulated tau spread into hippocampal neurons. In Aim 3, we will
confirm the cell type, which is selected in Aim 2, for the export of EVs into hippocampal neurons by cell type-
specific deletion of P2rx7 or Tsg101, an exosome synthesis molecule, and validate if P2RX7-mediated EV
secretion are responsible for tau propagation using AAV-based tau propagation mouse model. Successful
completion of this study will enhance our understanding of molecules that mediates secretion of EVs from glia
to neurons in vitro and in vivo, and identify novel targets for AD.

## Key facts

- **NIH application ID:** 10573168
- **Project number:** 5R01AG066429-04
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Tsuneya Ikezu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10573168

## Citation

> US National Institutes of Health, RePORTER application 10573168, Targeting emerging P2RX7 signaling pathways in animal models of Alzheimer's disease (5R01AG066429-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10573168. Licensed CC0.

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