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 A?, namely ApoE/A? complex, modulates A? levels and is implicated in A? clearance. C/EBP? is an inflammatory cytokines-regulated transcription factor that can be activated by A? as well. Interestingly, we have recently reported that C/EBP? 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 A? deposits and NFT aggregation and abolishes AD pathologies in various AD mouse models. In our preliminary studies, we found that C/EBP? binds ApoE promoter and dictates ApoE mRNA transcription during aging. Knockout of C/EBP? in 3xTg greatly reduces ApoE levels and senile plaques. On the other hand, ApoE4 but not E3 strongly activates C/EBP? in primary neurons. Blockage of ApoE4 interaction with its receptor diminishes this effect. Moreover, 27- hydroxycholesterol displays much stronger effect in stimulating C/EBP? than cholesterol in the presence of ApoE4. Hence, we hypothesize that ApoE4 and 27-oxycholesterol trigger C/EBP? 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/EBP? crosstalk will provide an innovative insight into the pathological roles of ApoE4 in AD onset and progression.
The ApoE protein plays many important roles, including the transport of cholesterol across different tissues and cells and clearance of amyloid ? (A?) from the brain, and ApoE4 is the major genetic risk factor for Alzheimer's disease (AD). The molecular mechanism of how ApoE4 contributes to AD pathogenesis remains unclear. In this grant application, we propose various experimentation to dissect its crosstalk with a cytokine- mediated transcription factor C/EBP?.