# Suppression of Glial Activation in Tau Transgenic Mice Through Inhibition of CRMP2 Phosphorylation: a Morphometric Analysis

## TL;DR

This study shows that inhibiting CRMP2 phosphorylation reduces glial activation in a mouse model of tauopathy, suggesting a potential treatment for Alzheimer's disease.

## Contribution

The study demonstrates that CRMP2 phosphorylation inhibition can suppress neuroinflammation in tauopathy models.

## Key findings

- Inhibiting CRMP2 phosphorylation normalized microglia and astrocyte activation in PS19 mice.
- CRMP2KI/KI mice showed suppressed Cox-2 expression in hippocampal neurons compared to PS19 mice.
- The results suggest CRMP2 phosphorylation inhibition may improve neuroinflammation in tauopathies.

## Abstract

Tauopathies, including Alzheimer’s disease (AD), are neurodegenerative diseases characterized by abnormal tau aggregation in neurons and glial cells. Various tauopathy mouse models have been developed, including PS19, a tau-overexpressing transgenic mouse model with the P301S mutation, in which glial activation has been reported prior to the accumulation of tau. In this mouse model, tau pathology was improved by the administration of the immunosuppressant FKB506, suggesting that inflammatory responses promote the progression of tau pathology. Our previous studies have shown that the inhibition of Collapsin response mediator protein 2 (CRMP2) phosphorylation suppresses inflammation and ameliorates pathological progression in spinal cord injury and MPTP-induced Parkinson’s disease models using CRMP2KI/KI mice, in which the phosphorylation site Ser522 was replaced with Ala. Therefore, we compared glial cell activation in male PS19 and PS19; CRMP2KI/KI mice using morphometric analysis at 5 months of age, before the onset of tau pathology. We found that the morphological changes caused by the activation of microglia and astrocytes were normalized by suppressing CRMP2 phosphorylation compared with those in PS19 mice. Cox-2 expression in hippocampal neurons was increased in PS19 mice, but this increase was suppressed in PS19; CRMP2KI/KI mice, suggesting that the suppression of CRMP2 phosphorylation in neurons is also involved in this process. These results suggest that the inhibition of CRMP2 phosphorylation may improve neuroinflammation in tauopathy.

The online version contains supplementary material available at 10.1007/s12017-025-08891-9.