Impaired hypoxic tolerance in APP23 mice: a dysregulation of neuroprotective globin levels

Abstract

Although neuroglobin confers neuroprotection against Alzheimer's disease (AD) pathology, its expression becomes downregulated in late‐stage AD. Here, we provide evidence that indicates that this decrease is associated with the AD‐linked angiopathy. While wild‐type mice of different ages show upregulated cerebral neuroglobin expression upon whole‐body hypoxia, APP23 mice exhibit decreased cerebral transcription of neuroglobin. Interestingly, transcription of cytoglobin, whose involvement in amyloid pathology still needs to be elucidated, follows a similar pattern. To further unravel the underlying mechanism, we examined the expression levels of the RE‐1‐silencing transcription factor (REST/NRSF) after identifying a recognition site for it in the regulatory region of both globins. Neuroglobin‐cytoglobin‐REST/NRSF expression correlations are detected mainly in the cortex. This raises the possibility of REST/NRSF being an upstream regulator of these globins.

Connecting the Dots in the Neuroglobin-Protein Interaction Network of an Unstressed and Ferroptotic Cell Death Neuroblastoma Model

“…This transcription factor represses genes involved in cell death and upsurges expression of neurotransmission-linked genes in the early stages of the AD pathology [21]. Besides, REST-Ngb expression correlations have already been described by us in cortices of APP23 mice [20]. Interestingly, we furthermore detected hNgb to bind to the 14-3-3 protein (YWHAZ).…”

“…This heme protein belongs to the globin family, scavenges ROS/RNS, and augments the threshold for apoptosis initiation (reviewed in [18]). We also recently correlated the expression levels of Ngb with those of repressor element 1-silencing transcription factor (REST/NRSF) [19,20]. Of interest, REST/NRSF represses genes that endorse cell death, oxidative stress, and amyloid β-protein toxicity [21].…”