Nature communicationsAug 27, 2025

Replacing brain immune cells in a Sandhoff disease mouse model shows immune cell enzyme is needed for neuron health

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Updated Jan 2, 2026

Abstract

Microglial replacement in a mouse model of Sandhoff disease improves neuronal health by restoring β-hexosaminidase activity and reversing neurodegenerative changes.

β-hexosaminidase, secreted by microglia, integrates into the lysosomes of neurons.
Treatment with bone marrow transplant and receptor inhibition replaces deficient microglia with healthy cells.
Replacement of microglia reverses gene signatures associated with cell death.
Behavioral improvements are observed alongside restored enzymatic activity and expression of β-hexosaminidase.
The intervention prevents the accumulation of toxic substrates and normalizes lysosomal function in neurons.

Simplified

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme (Hexb). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To investigate how a microglial gene is involved in neuronal homeostasis, here we show that β-hexosaminidase is secreted by microglia and integrated into the lysosomal compartment of neurons. To assess therapeutic relevance, we treat the HexbSD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces Hexbmicroglia with Hexb-sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores β-hexosaminidase enzymatic activity and Hexb expression, prevents substrate buildup, and normalizes neuronal lysosomal phenotypes, underscoring the critical role of myeloid-derived β-hexosaminidase in maintaining neuronal health and establishing microglial replacement as a potential LSD therapy. -/--/-