Involvement of Hepcidin in Cognitive Damage Induced by Chronic Intermittent Hypoxia in Mice

Abstract

Obstructive sleep apnea (OSA) patients exhibit different degrees of cognitive impairment, which is related to the activation of reactive oxygen species (ROS) production by chronic intermittent hypoxia (CIH) and the deposition of iron in the brain. As a central regulator of iron homeostasis, whether hepcidin is involved in OSA-induced cognitive impairment has not been clarified. In order to simulate OSA, we established the mouse model by reducing the percentage of inspired O2 (FiO2) from 21% to 5%, 20 times/h for 8 h/day. We found hepcidin was rising during CIH, along with increasing iron levels and neuron loss. Then, we constructed a mouse with astrocyte-specific knockdown hepcidin gene (shHamp). During CIH exposure, the shHamp mice showed a lower level of total iron and neuronal iron in the hippocampus, via stabilizing ferroportin 1 (FPN1) and decreasing L-ferritin (FTL) levels, when compared with wild-type (WT) mice. Furthermore, the shHamp mice showed a decrease of ROS by downregulating the elevated NADPH oxidase (NOX2) and 4-hydroxynonenal (4-HNE) levels mediated by CIH. In addition, the shHamp mice presented improved cognitive deficit by improving synaptic plasticity and BDNF expression in the hippocampus when subjected to CIH. Therefore, our data revealed that highly expressed hepcidin might promote the degradation of FPN1, resulting in neuronal iron deposition, oxidative stress damage, reduced synaptic plasticity, and impaired cognitive performance during CIH exposure.

Abnormal brain iron accumulation in obstructive sleep apnea: A quantitative MRI study in the HypnoLaus cohort

“…To our knowledge, no previous neuroimaging or postmortem study has provided results on the association between obstructive sleep apnea and iron in brain tissue in humans. Only a few recent mice investigations have reported on increased iron accumulation in the hippocampus after exposure to an intermittent hypoxia protocol (An et al, 2020 ; Zhao et al, 2021 ). Therefore, it is difficult to speculate on the casual link between obstructive sleep apnea and iron changes, but some hypotheses could be formulated.…”

Huperzine A-Liposomes Efficiently Improve Neural Injury in the Hippocampus of Mice with Chronic Intermittent Hypoxia

“…Morris water maze (MWM) was used to evaluate spatial memory, as previously described. 4 As shown in Figure 1A , two days of visible platform training were used to adapt the mice to the aquatic labyrinth. Then, the following five days of hidden platform training were used to place the navigation test.…”

“…Then, the samples were prepared according to standard procedures as previously described. 4 The sections were observed under a Hitachi HT7800/HT7700 electron microscope.…”

“… 2 The adverse outcomes of cognitive domains manifest as daytime sleepiness, lower attention, poor episodic memory, reduced responsiveness and working memory, behavioral problems, etc. 3 , 4 Currently, the OSA population is increasing, and this disorder is becoming a global health problem. 5 However, most individuals remain unaware of the health problem, and 80% do not receive a diagnosis and treatment.…”

“… 17 Our previous research found that iron overload was involved in the neural damage induced by CIH. 4 , 16 Transferrin-transferrin receptor 1 (Tf-TfR1) is the main form of iron uptake, and inhibition of TfR1 expression attenuates the iron content in the hippocampus of CIH mice. 16 At the same time, hepcidin is the central iron regulatory factor and regulates iron exporters by causing ubiquitination and degradation of Ferroportin1 (FPN1), the sole iron exporter protein.…”