ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction
An important component of neuron-glia coupling is the transport and delivery of neuron-derived lipids to glial lipid droplets. This pathway is important as failure to store incoming lipids in glial lipid droplets exacerbates neurodegeneration. ApoE4, a risk factor for Alzheimer's disease, impairs this transport pathway. But how ApoE4 affects lipid trafficking in glia and whether these alterations…
ApoE4, a known risk factor for Alzheimer's disease, disrupts the process of transporting and storing lipids in glial lipid droplets within astrocytes. This decline in lipid trafficking contributes to neurodegeneration. The study reveals that ApoE4 particles hinder endolysosomal function, leading to the accumulation of lipofuscin and the disruption of lipid droplet formation in cultured primary astrocytes.
However, the researchers discovered that restoring the impaired lysosomal function using PCSK9, a protein that prevents lipid receptor recycling and reduces ApoE4 internalization, can recover lipid droplets. Similarly, repairing endolysosomal function in the presence of ApoE4 also enables the recovery of lipid droplets. These findings shed new light on how ApoE4 dysregulates lipid storage and provide potential mechanisms to correct these defects.
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