Protective mechanisms against Alzheimer's Disease in APOE3-Christchurch homozygous astrocytes

Tian, X.; Rivera, E. K.; Nikitina, A. A.; Hwang, I.; Smith, J. A.; Cho, Y. J.; Sala-Jarque, J.; DeBose, A.; Andriola, C.; Gollan-Meyer, T.; Kosik, K. S.

doi:10.1101/2025.01.21.634115

bioRxiv · 10.1101/2025.01.21.634115

Protective mechanisms against Alzheimer's Disease in APOE3-Christchurch homozygous astrocytes

Tian, X.·Rivera, E. K.·Nikitina, A. A.·Hwang, I.·Smith, J. A.·Cho, Y. J.·Sala-Jarque, J.·DeBose, A.·Andriola, C.·Gollan-Meyer, T.·Kosik, K. S.

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Abstract

The APOE3-Christchurch (APOE3-Ch) variant has been linked to reduced Alzheimers Disease (AD) risk, but its protective mechanisms remain unclear. This study explores the neuroprotective phenotype of APOE3-Ch astrocytes, focusing on lipid metabolism and tau processing. APOE3-Ch astrocytes demonstrate enhanced tau oligomer uptake via HSPG- and LRP1-mediated pathways, facilitated by elevated HSPG expression, and achieve superior tau degradation through lysosomal pathways and proteasomal pathways, in contrast to wild-type astrocytes, which primarily use proteasomal mechanisms. Transcriptomic analysis reveals upregulation of genes involved in endocytosis and cell projection assembly, explaining enhanced tau uptake and clearance in APOE3-Ch astrocytes. Lipidomic profiling identifies reduced levels of pathological lipids such as ceramides and gamma-linolenic acid (GLA), potentially mitigating neuroinflammation. These findings provide insight into the protective mechanisms of APOE3-Ch astrocytes and underscore their potential as therapeutic targets for tauopathy and neurodegeneration in AD. TeaserAPOE3-Christchurch astrocytes enhance tau clearance and mitigate neurotoxic lipid accumulation, unveiling protective mechanisms against Alzheimers.

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Tian, X., Rivera, E. K., Nikitina, A. A., Hwang, I., Smith, J. A., Cho, Y. J., Sala-Jarque, J., DeBose, A., Andriola, C., Gollan-Meyer, T., Kosik, K. S.. 2025-01-21. Protective mechanisms against Alzheimer's Disease in APOE3-Christchurch homozygous astrocytes. https://doi.org/10.1101/2025.01.21.634115

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