C/EBP beta/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer's disease

• Type of Material: Article
• Authors: Jianming Liao, Emory University; Guiqin Chen, Emory University; Xia Liu, Emory University; Zheng Zachory Wei, Emory University; Shan Ping Yu, Emory University; Qianxue Chen, Renmin Hospital of Wuhan University; Keqiang Ye, Emory University
• Language: English
• Date: 2022-04-14
• Publisher: SPRINGERNATURE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41380-022-01556-0
• Title of Journal or Parent Work: MOLECULAR PSYCHIATRY
• Volume: 27
• Issue: 7
• Start Page: 3034
• End Page: 3046
• Keywords: Life Sciences & Biomedicine; BLOOD-FLOW; A-BETA; Neurosciences & Neurology; CHOLESTEROL; Biochemistry & Molecular Biology; INFLAMMATION; APO-E; Science & Technology; APOLIPOPROTEIN-E; Psychiatry; MOUSE MODEL; COGNITIVE IMPAIRMENT; CEREBRAL AMYLOID ANGIOPATHY; MICE; Neurosciences

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.