Friday, April 26, 2024
4/26/2024
ApoE4 is the major genetic risk factor for Alzheimer's disease (AD) pathogenesis. In the central nervous system (CNS), ApoE is mainly produced by glia and astrocytes and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor (LDLR) gene family. ApoE isoform- specific interactions with Aß, namely ApoE/Aß complex, modulates Aß levels and is implicated in Aß clearance. C/EBPß is an inflammatory cytokines-regulated transcription factor that can be activated by Aß as well. Interestingly, we have recently reported that C/EBPß acts as an age-dependent transcription factor for delta-secretase (AEP, also called legumain). This crucial protease cleaves both APP and Tau in human AD brains and AD mouse models, promoting amyloidogenic pathway and neurofibrillary tangle (NFT) formation. Inactivation of delta-secretase substantially decreases Aß deposits and NFT aggregation and abolishes AD pathologies in various AD mouse models. In our preliminary studies, we found that C/EBPß binds ApoE promoter and dictates ApoE mRNA transcription during aging. Knockout of C/EBPß in 3xTg greatly reduces ApoE levels and senile plaques. On the other hand, ApoE4 but not E3 strongly activates C/EBPß in primary neurons. Blockage of ApoE4 interaction with its receptor diminishes this effect. Moreover, 27- hydroxycholesterol displays much stronger effect in stimulating C/EBPß than cholesterol in the presence of ApoE4. Hence, we hypothesize that ApoE4 and 27-oxycholesterol trigger C/EBPß activation, which feeds back and upregulates ApoE transcription in AD pathogenesis. Consequently, this vicious loop may facilitate AD pathologies via escalating delta-secretase levels. To define the molecular mechanisms between ApoE4/C/EBPß crosstalk will provide an innovative insight into the pathological roles of ApoE4 in AD onset and progression.
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