# Astrocytic PYGM attenuates tau pathology by promoting lactate‐mediated neuroprotection

## TL;DR

Astrocytic PYGM helps reduce tau-related brain damage by supporting lactate-based communication between brain cells.

## Contribution

The study reveals a novel role for astrocytic PYGM in mitigating tau pathology through lactate-mediated neuroprotection.

## Key findings

- PYGM expression increases in FTLD-U patients and tauP301S mice during disease progression.
- Astrocytic PYGM deficiency worsens tau pathology and cognitive decline in mice.
- PYGM overexpression and lactate supplementation protect against tau-related brain damage.

## Abstract

Tauopathies are characterized by hyperphosphorylated tau accumulation and neurodegeneration. Although astrocytic metabolism is known to support neuronal health, the role of astrocytic glycogen metabolism, particularly the glycogenolytic enzyme PYGM (glycogen phosphorylase, muscle associated), in tauopathies remains unclear.

We analyzed PYGM expression in the brains of frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U) patients and tauP301S transgenic (PS19) mice, assessed tauopathy‐related phenotypes in male PS19 mice with astrocyte‐specific PYGM knockout or overexpression, studied the effects of PYGM knockdown on astrocytes and neurons, and evaluated the effects of lactate supplementation on male PS19 mice.

PYGM expression increased in the brains of FTLD‐U patients and the astrocytes of PS19 mice. Astrocytic PYGM deficiency impaired mouse cognition, exacerbated tauopathy‐related phenotypes in male PS19 mice, and disrupted astrocyte‐neuron metabolic coupling. PYGM overexpression and lactate supplementation attenuated tauopathy‐related phenotypes in male PS19 mice.

Astrocytic PYGM supports neuronal health by sustaining lactate‐mediated astrocyte‐neuron metabolic coupling. Enhancing astrocytic glycogenolysis may be beneficial in tauopathies.

PYGM (glycogen phosphorylase, muscle associated) expression increases in the brains of frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U) patients and the tauP301S transgenic (PS19) tauopathy model mice at pathological stages.Astrocytic PYGM deficiency impairs cognitive function in mice.Astrocytic PYGM deficiency exacerbates tauopathy‐related phenotypes and reduces lactate production in PS19 mice.Overexpression of PYGM in astrocytes and lactate supplementation confer protection in PS19 mice.

PYGM (glycogen phosphorylase, muscle associated) expression increases in the brains of frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U) patients and the tauP301S transgenic (PS19) tauopathy model mice at pathological stages.

Astrocytic PYGM deficiency impairs cognitive function in mice.

Astrocytic PYGM deficiency exacerbates tauopathy‐related phenotypes and reduces lactate production in PS19 mice.

Overexpression of PYGM in astrocytes and lactate supplementation confer protection in PS19 mice.