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Published on: October 30, 2018
C/EBPβ/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer's disease
Jianming Liao1,2, Guiqin Chen1,3, Xia Liu1
1Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Insights
The C/EBPβ/AEP pathway links atherosclerosis and Alzheimer's disease by mediating vascular pathology. This signaling pathway impacts cholesterol, foam cell formation, and cognitive function in mouse models.
Area of Science:
- Neuroscience
- Cardiovascular Biology
- Immunology
Background:
- Atherosclerosis (ATH) and Alzheimer's disease (AD) are age-related inflammatory conditions with shared molecular pathways.
- The transcription factor C/EBPβ and asparagine endopeptidase (AEP) are implicated in both ATH and AD.
- The precise role of C/EBPβ/AEP signaling in connecting ATH to AD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate whether C/EBPβ/AEP signaling mediates ATH pathology and links ATH to AD.
- To elucidate the role of this pathway in vascular pathology and cognitive decline.
Main Methods:
- Utilized ApoE-/- and 3xTg AD mouse models, including 3xTg/ApoE-/- double knockouts.
- Manipulated C/EBPβ and AEP levels via gene deletion or knockdown.
- Assessed macrophage cholesterol load, foam cell formation, aortic lesions, serum LDL levels, cerebral blood flow, and cognitive function.
Main Results:
- Inactivation of C/EBPβ/AEP diminished cholesterol load, reduced foam cell formation, and decreased aortic lesions in high-fat-diet-fed ApoE-/- mice.
- In 3xTg/ApoE-/- mice, C/EBPβ or AEP depletion attenuated ATH markers, improved cerebral blood flow and vessel length, and restored cognitive function.
- ApoE knockdown in 3xTg mice worsened AD pathology and cognitive deficits, effects alleviated by C/EBPβ/AEP pathway inactivation.
Conclusions:
- The C/EBPβ/AEP signaling pathway is a critical mediator connecting atherosclerosis to Alzheimer's disease.
- This pathway influences vascular pathology, including cholesterol metabolism and lesion formation.
- Targeting the C/EBPβ/AEP pathway holds potential for treating co-occurring ATH and AD.
Abstract:
Atherosclerosis (ATH) and Alzheimer's disease (AD) are both age-dependent inflammatory diseases, associated with infiltrated macrophages and vascular pathology and overlapping molecules. C/EBPβ, an Aβ or inflammatory cytokine-activated transcription factor, and AEP (asparagine endopeptidase) are intimately implicated in both ATH and AD; however, whether C/EBPβ/AEP signaling couples ATH to AD pathogenesis remains incompletely understood. Here we show that C/EBPβ/AEP pathway mediates ATH pathology and couples ATH to AD. Deletion of C/EBPβ or AEP from primary macrophages diminishes cholesterol load, and inactivation of this pathway reduces foam cell formation and lesions in aorta in ApoE-/- mice, fed with HFD (high-fat-diet). Knockout of ApoE from 3xTg AD mouse model augments serum LDL and increases lesion areas in the aorta. Depletion of C/EBPβ or AEP from 3xTg/ApoE-/- mice substantially attenuates these effects and elevates cerebral blood flow and vessel length, improving cognitive functions. Strikingly, knockdown of ApoE from the hippocampus of 3xTg mice decreases the cerebral blood flow and vessel length and aggravates AD pathologies, leading to cognitive deficits. Inactivation of C/EBPβ/AEP pathway alleviates these events and restores cognitive functions. Hence, our findings demonstrate that C/EBPβ/AEP signaling couples ATH to AD via mediating vascular pathology.
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