Microglial apolipoprotein E particles contribute to neuronal senescence and synaptotoxicity

Apolipoprotein E (apoE) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). In the brain, apoE is predominantly expressed and secreted by astrocytes, but is dramatically up-regulated in microglia under AD-associated conditions. Although the function of astrocytic apoE has been widely investigated, whether and how apoE particles derived from different types of glia differ in biological features and function remains elusive. Here, we show that apoE particles derived from astrocytes and microglia exhibit dissimilar sizes. Microglial apoE particles impaired neurite growth and synapses and promoted neuronal senescence, whereas GPNMB-deficient microglial apoE particles abolished these detrimental effects. These findings provide direct evidence supporting that microglia-derived apoE particles contribute to neuronal senescence and toxicity. To explore how apoE particles affect transcriptome of neurons, we treated primary neurons with apoE particle for 24h. We then performed gene expression profiling analysis using data obtained from RNA-Seq of two treatment. Comparative gene expression of RNA-seq data for primary neuron treated with microglia apoE particle and astrocytic apoE particle.