C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease

Abstract

Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer’s disease (AD). However, how aging contributes to an increase in delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus

“…MAO-A generates H 2 O 2 and DOPEGAL, when it metabolizes NE. Both H 2 O 2 and DOPEGAL induce AEP activation and trigger cell death, and we have shown that the transcription factor, CEBP-β, regulates the expression of AEP (40). Conceivably, there is positive feedback between NE metabolism and CEBP-β, whereby increased levels of MAO-A and H 2 O 2 activate CEBP-β, which, in turn, induces further MAO-A and AEP expression.…”

Age-Related Gene Expression Signature in Rats Demonstrate Early, Late, and Linear Transcriptional Changes from Multiple Tissues

“…In the brain, these changes are sugges-tive of age-related induction of neuro-inflammation and activation of glia. C/EBPb (coded by the Cebpb gene) is a basicleucine zipper DNA-binding protein that controls expression of cytokines and other pro-inflammatory genes and induces pathways that are critical for glia activation (Bradley et al, 2003;Wang et al, 2018). Apart from being implicated in neuro-inflammation, C/EBPb controls expression of delta-secretase enzyme, which is thought to contribute to the pathology in Alzheimer's disease by cleaving both Tau and beta-amyloid precursor protein .…”

Age-related Gene Expression Signatures (AGES) in rats demonstrate early, late, and linear transcriptional changes from multiple tissues

“…In the brain, these changes are suggestive of age-related induction of neuro-inflammation and activation of glia. C/EBPβ (coded by the Cebpb gene) is a basic-leucine zipper DNA-binding protein that controls expression of cytokines and other pro-inflammatory genes, and induces pathways that are critical for glia activation (Bradley et al, 2003; Wang et al, 2018). Apart from being implicated in neuro-inflammation, C/EBPβ controls expression of delta-secretase enzyme, which is thought to contribute to the pathology in Alzheimer’s disease by cleaving both Tau and beta-amyloid precursor protein (Wang et al, 2018).…”

“…C/EBPβ (coded by the Cebpb gene) is a basic-leucine zipper DNA-binding protein that controls expression of cytokines and other pro-inflammatory genes, and induces pathways that are critical for glia activation (Bradley et al, 2003; Wang et al, 2018). Apart from being implicated in neuro-inflammation, C/EBPβ controls expression of delta-secretase enzyme, which is thought to contribute to the pathology in Alzheimer’s disease by cleaving both Tau and beta-amyloid precursor protein (Wang et al, 2018). ISG15 (interferon stimulated gene 15) (Kessler et al, 1988), which also was upregulated in every tissue examined, is a ubiquitin-like protein, and its expression is induced by type-I IFNs and by p53 (Huang and Bulavin, 2014) (Park et al, 2016).…”