ApoE isoforms differentially regulates cleavage and secretion of BDNF.

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for sporadic or late onset Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) is decreased by 3 to 4-fold in the brains of AD patients at autopsy. ApoE4 mice also have reduced BDNF levels. However, there have been no reports relating the different ApoE isoforms or AD to differential regulation of BDNF. Here we report that in the hippocampal regions of AD patients both prepro-BDNF and pro-BDNF expression showed a 40 and 60% decrease respectively compared to that expression in the hippocampi of age-matched control patients. We further report that ApoE isoforms differentially regulate maturation and secretion of BDNF from primary human astrocytes. After 24 h, ApoE3 treated astrocytes secreted 1.75- fold higher pro-BDNF than ApoE2-treated astrocytes, and ApoE2-treated astrocytes secreted 3-fold more mature-BDNF (m-BDNF) than ApoE3-treated astrocytes. In contrast, ApoE4-treated cells secreted negligible amounts of m-BDNF or pro-BDNF. ApoE2 increased the level of intracellular pre-pro BDNF by 19.04 ± 6.68%, while ApoE4 reduced the pre-pro BDNF by 21.61 ± 5.9% compared to untreated cells. Similar results were also seen in ApoE2, ApoE3 or ApoE4 treated cells at 4 h. Together, these results indicate that an ApoE2 or ApoE3 mediated positive regulation of BDNF may be protective while ApoE4 related defects in BDNF processing could lead to AD pathophysiology. These interactions of the ApoE isoforms with BDNF may help explain the increased risk of AD associated with the ApoE4 isoform.