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bioRxiv · 10.1101/2025.10.24.684364

APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons

Halim, D. O.·Di Biase, E.·Rajon, A.·Jordi, L.·Hallett, P.·Isacson, O.
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Abstract

Lipid abnormalities are emerging as key pathogenic mechanisms in neurodegenerative diseases such as Alzheimers, Parkinsons and Lewy body dementia. Astrocytes in the brain provide APOE proteins and influence neuronal metabolism and health. Using live cell imaging and objective neurite imaging techniques, we show that following induction of cellular lipid (cholesterol and triglycerides) load by inhibiting the lysosomal cholesterol transport protein NPC1 in human neuron-astrocyte co-cultures, that human astrocytes CRISPR edited to be either APOE3 or 4 variants have different effects on rescuing dystrophic neurites, where axons and dendrites of nerve cells become disfigured. APOE3, but not APOE4 or APOEKO, astrocytes prevented cholesterol and lipid induced neurite damage in APOE4 neurons. In the media of APOE3 co-cultured astrocytes with neurons the HDL-like particles were larger and presumably more lipidated than equivalent APOE4 co-cultures. This discovery highlights that living APOE3 astrocytes control key biological mechanisms by physiologically enhancing lipid cellular homeostasis, that can rescue lipid-induced neurite structural abnormalities relevant to Alzheimers disease and neurodegenerative diseases. Significance statementNeurodegenerative diseases like Alzheimers (AD) are often defined by abnormal protein aggregates, but growing evidence points to lipid dysfunction as a key driver, especially in APOE4 carriers, the strongest genetic risk factor for AD. We developed a live cell imaging based human cell culture model using isogenic iPSC-derived neurons and astrocytes (APOE3, APOE4, or APOE knockout) to study this. By blocking cholesterol export via NPC1 inhibition, we mimicked lysosomal lipid stress and found that APOE3 astrocytes uniquely protected APOE4 neurons from forming abnormal neurite swellings. These APOE3 astrocytes produced larger HDL-like particles than APOE4 that supported neuronal lipid balance. Our results show that APOE3 astrocytes can rescue APOE4-related cellular dysfunction, offering a potential path for therapy and biomarker discovery.

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Halim, D. O., Di Biase, E., Rajon, A., Jordi, L., Hallett, P., Isacson, O.. 2025-10-24. APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons. https://doi.org/10.1101/2025.10.24.684364

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