Lower levels of apoE4 than apoE3 have been reported in human apoE4 and apoE3 knock-in mouse brains39 and in samples of human brain and cerebrospinal fluid1. Indeed, we found that cultured human neurons have ~35% less intracellular apoE4 than apoE3 and secrete ~60% less apoE4 than apoE3. Consequently, the ratio of intracellular apoE to secreted apoE was over 20% higher in apoE4/4 neurons, suggesting that apoE4 tends to be retained inside neurons. These findings might reflect a prolonged retention time of apoE4 in the endoplasmic reticulum and the Golgi apparatus, as reported in cultured rat neuronal cells37. ApoE fragments accumulate in the brains of neuron-specific apoE4 transgenic mice and AD patients carrying apoE417,18. However, our study shows for the first time in cultured human neurons that apoE4 is more susceptible than apoE3 to proteolytic cleavage, generating more neurotoxic fragments.
