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| Item Type: | Preprint |
|---|---|
| Title: | Tau spreading coordinates intercellular lipid flux enhancing neuronal resilience to lipid toxicity |
| Creators: |
Oliveras Martinez, Anna  ORCID: https://orcid.org/0000-0002-5880-5245, Ibatici, Davide ORCID: https://orcid.org/0009-0007-8452-0335, Calvo Noriega, Maria ORCID: https://orcid.org/0000-0002-1097-2618, Mastrobuoni, Guido ORCID: https://orcid.org/0000-0003-4509-1295, Forbes, Martin ORCID: https://orcid.org/0000-0001-7775-8352, Santiago Padilla, Leandro Manuel ORCID: https://orcid.org/0000-0002-0873-7205, Aykul, Melisa ORCID: https://orcid.org/0009-0000-3837-9771, Horvatovic, Kamelija ORCID: https://orcid.org/0000-0002-3424-1326, Rusu, Mara-Camelia ORCID: https://orcid.org/0000-0002-8369-3580, Patsonis, Melina ORCID: https://orcid.org/0009-0000-6287-772X, Jutras-Dube, Laurent ORCID: https://orcid.org/0000-0003-4323-2840, Rossius, Jana ORCID: https://orcid.org/0009-0000-6011-9714, Cerda-Jara, Cledi Alicia ORCID: https://orcid.org/0000-0003-1783-5533, Bahry, Ella ORCID: https://orcid.org/0000-0002-6358-2576, Broichhagen, Johannes ORCID: https://orcid.org/0000-0003-3084-6595, Schmidt, Deborah ORCID: https://orcid.org/0000-0002-8621-9438, Metzger, Jakob ORCID: https://orcid.org/0000-0001-6813-4425, Rajewsky, Nikolaus ORCID: https://orcid.org/0000-0002-4785-4332, Kunz, Severine ORCID: https://orcid.org/0000-0002-0131-3506, Rybak-Wolf, Agnieszka ORCID: https://orcid.org/0000-0002-1192-5290, Kempa, Stefan ORCID: https://orcid.org/0000-0002-0696-9299 and Birol, Melissa ORCID: https://orcid.org/0000-0003-3397-8446
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| Abstract: | The presence of intrinsically disordered proteins (IDPs) in the extracellular environment of the brain suggests that protein disorder may serve functions beyond those confined to the intracellular space. Tau, a prototypical IDP linked to tauopathies, a class of neurodegenerative diseases, is continuously released and spreads between cells in the brain, yet the biological significance of this extracellular phase remains unresolved. Here, we show that spreading tau coordinates neutral lipid homeostasis by promoting neuronal lipid efflux and enhancing resilience to lipid toxicity. Integrating transcriptomics and lipidomics, we demonstrate that tau spreading reprograms lipid transport pathways and triggers redistribution of triacylglycerol pools, remodeling neutral lipid metabolism. Mechanistically, cellular uptake of spreading tau drives its accumulation within neutral lipid-rich compartments and promotes neuronal lipid efflux. The exported lipids are enriched in peroxidized species that are subsequently transferred to astrocytes, reducing neuronal lipid stress and revealing a pathway through which tau regulates lipid homeostasis. Our findings reframe spreading tau as a regulator of intercellular lipid flux and position protein disorder as an active mediator of cell-to-cell communication in coordinating tissue metabolism. Loss of this homeostatic function is likely to contribute to the early metabolic dysfunction associated with tauopathy. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.07.30.741734 |
| Date: | 4 August 2026 |
| Official Publication: | https://doi.org/10.64898/2026.07.30.741734 |
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