# PRMT3‐Mediated H4R3me2a Promotes Primary Age‐Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron

## TL;DR

This study finds that PRMT3 causes tau hyperphosphorylation in a brain disease called primary age-related tauopathy, suggesting PRMT3 inhibitors could be a new treatment.

## Contribution

The study identifies PRMT3-mediated H4R3me2a as a novel driver of tau hyperphosphorylation in primary age-related tauopathy.

## Key findings

- PRMT3 drives tau hyperphosphorylation via H4R3me2a and miR-448 upregulation.
- PRMT3 inhibition with SGC707 reduces tau pathology and neuronal dysfunction.
- The PRMT3/H4R3me2a/miR-448 axis suppresses IGF1R via epigenetic regulation.

## Abstract

Primary age‐related tauopathy (PART) and Alzheimer's disease (AD) both exhibit 3R/4R hyperphosphorylated tau‐positive neurofibrillary tangles (NFTs) within the hippocampal–entorhinal system. Notably, PART patients show a higher degree of tau hyperphosphorylation in the entorhinal cortex (EC) than AD, yet the molecular mechanisms driving Aβ‐independent tau hyperphosphorylation in PART remain poorly understood. Herein, through transcriptomic profiling of postmortem EC tissues and in vitro and in vivo functional validation, the present study identifies protein arginine methyltransferase 3 (PRMT3) as a critical driver of tau hyperphosphorylation. Mechanistically, PRMT3‐mediated tau hyperphosphorylation is dependent on asymmetric dimethylation of histone H4 at arginine 3 (H4R3me2a), which upregulates miR‐448. Elevated miR‐448 specifically targets and suppresses IGF1R, leading to downstream GSK3β activation and subsequent tau hyperphosphorylation through PI3K/AKT/GSK3β signaling. Treatment with SGC707, a selective PRMT3 inhibitor, effectively reduces tau hyperphosphorylation and demonstrates therapeutic promise for PART and potentially other tauopathies. Collectively, this study defines the PRMT3/H4R3me2a/miR‐448 axis as a critical regulatory pathway in tau hyperphosphorylation within PART, underscoring the potential of PRMT3 inhibition as a targeted therapeutic strategy for tauopathies.

This study identifies PRMT3‐mediated H4R3me2a as a critical driver of tau hyperphosphorylation in primary age‐related tauopathy. Mechanistic insights reveal that the PRMT3/H4R3me2a/miR‐448 axis suppresses IGF1R expression via epigenetic regulation, further dysregulating the PI3K/AKT/GSK3β pathway. Therapeutic potential is highlighted with PRMT3 inhibition by SGC707, reducing tau pathology and reversing neuronal dysfunction in cellular and mouse models.