Astrocytic PYGM attenuates tau pathology by promoting lactate-mediated neuroprotection.

INTRODUCTION: 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. METHODS: We analyzed PYGM expression in the brains of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) patients and tau(P301S) 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. RESULTS: 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. DISCUSSION: Astrocytic PYGM supports neuronal health by sustaining lactate-mediated astrocyte-neuron metabolic coupling. Enhancing astrocytic glycogenolysis may be beneficial in tauopathies.