Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis

Zhu, Ziling; Liu, Yandong; Gong, Yan; Wei, Jin; Topchiy, Elena; Turdi, Subat; Gao, Yuefeng; Culver, Bruce; Wang, Shuyi; Ge, Wei; Zha, Wenliang; Ren, Jun; Pei, Zhaohui; Qin, Xing

doi:10.1038/s41401-021-00635-2

Cited by 67 publications

(38 citation statements)

References 61 publications

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“…In our study, the activation of the neuronal ferroptosis in the cerebrum after acute hypobaric hypoxia was observed and may be caused by the cerebral FA accumulation. Though the exact mechanisms needed further exploration, ALDH2 inhibition can directly promote ferroptosis in animal models 42 43 while increased in ALDH2 KO mice 44 …”

Section: Discussionmentioning

confidence: 99%

Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

et al. 2022

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Acute high-altitude hypoxia exposure causes multiple adverse neurological consequences, including paralysis, blindness, sleep disturbance, mental disorder, and cognitive impairment. 1 Intellectual abilities such as concentration, perception, executive function, learning, and memory can be impaired, 2 which are caused by neuronal damage due to oxidative stress, inflammation, and other mechanisms. 3 However, the exact cellular and molecular mechanism of neurological dysfunction remains unclear. Therefore, there are no

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Section: Discussionmentioning

confidence: 99%

Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

et al. 2022

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“…Inhibition of Acsl4 expression reduces inflammatory responses, blood–brain barrier (BBB) damage, oxidative stress, and increases the number of surviving neurons after SAH 52 . Acsl4 significantly increases protein damage, lipid peroxidation markers and related signaling molecules in hearts from AD mice 53 . Our results showed significantly low Acsl4 (ENSMUST00000112903) in ADF as compared to ADNS, suggesting that fasudil alleviates the impairment caused by Acsl4 in AD mice.…”

Section: Discussionmentioning

confidence: 92%

Transcriptome analysis of fasudil treatment in the APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer’s disease

Yan

Gao

et al. 2022

Sci Rep

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Alzheimer's disease (AD) is the most common cause of progressive dementia. In the present study, we showed hippocampal tissue transcriptome analysis in APPswe/PSEN1dE9 (APP/PS1, AD model) mice treated with fasudil (ADF) and compared with AD mice treated with saline (ADNS) and wild type mice (WT). The competing endogenous RNA (ceRNA) network was constructed and validated the differential expression of mRNA, lncRNA, miRNA, and circRNA. Our study showed differentially expressed mRNAs (DEMs) between WT and ADNS, while enriched in cell growth and death and nervous system pathways. DEMs between ADNS-ADF were enriched in the nervous system, glycosaminoglycan biosynthesis-keratan sulfate (KS) and Quorum sensing pathways. We validated four genes with RT-PCR, whereas enrichment of Acyl-CoA Synthetase Long Chain Family Member 4 (Acsl4, ENSMUST00000112903) in Quorum sensing pathways, and BTG anti-proliferation factor 1 (Btg1, ENSMUST00000038377) in RNA degradation pathways were conducted. Expression of these two genes were higher in ADNS, but were significantly reduced in ADF. Histone H4 transcription factor (Hinfp, ENSMUST00000216508) orchestrate G1/S transition of mitotic cell cycle and co-expressed with mmu-miR-26a-2-3p-mediated ceRNA and mmu-miR-3065-5p-mediated ceRNA; Wnt family member 4 (Wnt4, ENSMUST00000045747) was enriched in mTOR, Hippo and Wnt signaling pathway. Expression of these two genes were significantly lower in ADNS, and fasudil treatment reverse it. The present studies demonstrated four genes: Acsl4, Btg1, Hinfp, Wnt4 could be potential biomarkers of AD and the targets of fasudil treatment. These results will pave a novel direction for future clinic studies for AD and fasudil treatment.

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“…In addition, it is unknown whether cell ferroptosis is a potential target by which Alda-1 alleviates IR-induced organ injury. However, a recent study demonstrated for the first time that Alda-1 could rescue cardiac contractile dysfunction induced by Alzheimer's disease through the inhibition of ACSL4-dependent ferroptosis ( 27 ). In the present study, significantly increased iron deposition, MDA and 4-HNE contents, and ACSL4 expression, and meanwhile significantly decreased GSH content and GPX4 expression were observed in the kidney and intestine in those resuscitated animals, which indicated the occurrence of cell ferroptosis in these two organs after CA and resuscitation.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Alda-1 Treatment on Renal and Intestinal Injuries After Cardiopulmonary Resuscitation in Pigs

Gao

Shao

et al. 2022

Front. Med.

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AimAfter successful cardiopulmonary resuscitation (CPR), most survivors will develop acute kidney injury and intestinal barrier dysfunction, both of which contribute to the poor outcomes of cardiac arrest (CA) victims. Recently, the aldehyde dehydrogenase 2 (ALDH2) agonist, Alda-1 was shown to effectively alleviate regional ischemia/reperfusion injury of various organs. In the present study, we investigated the effects of Alda-1 treatment on renal and intestinal injuries after CA and resuscitation in pigs.MethodsTwenty-four male domestic pigs were randomly divided into one of the three groups: sham (n = 6), CPR (n = 10), or CPR+Alda-1 (n = 8). CA was induced and untreated for 8 min, and then CPR was performed for 8 min in the CPR and CPR+Alda-1 groups. At 5 min after resuscitation, a dose of 0.88 mg/kg of Alda-1 was intravenously administered in the CPR+Alda-1 group. The biomarkers of renal and intestinal injuries after resuscitation were regularly measured for a total of 24 h. Subsequently, the animals were euthanized, and then renal and intestinal tissues were obtained for the measurements of ALDH2 activity and expression, and cell apoptosis and ferroptosis.ResultsFive of the 10 animals in the CPR group and six of the eight animals in the CPR+Alda-1 group were successfully resuscitated. After resuscitation, the levels of biomarkers of renal and intestinal injuries were significantly increased in all animals experiencing CA and resuscitation compared with the sham group; however, Alda-1 treatment significantly alleviated renal and intestinal injuries compared to the CPR group. Post-resuscitation ALDH2 activity was significantly decreased and its expression was markedly reduced in the kidney and intestine in those resuscitated animals compared with the sham group; nevertheless, both of them were significantly greater in those animals receiving Alda-1 treatment compared to the CPR group. In addition, renal, intestinal apoptosis and ferroptosis after resuscitation were observed in the CPR and CPR+Alda-1 groups, in which both of them were significantly milder in the CPR+Alda1 group than in the CPR group.ConclusionsThe activation of ALDH2 by Alda-1 treatment significantly alleviated post-resuscitation renal and intestinal injuries through the inhibition of cell apoptosis and ferroptosis in a pig model of CA and resuscitation.

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Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis

Cited by 67 publications

References 61 publications

Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

Transcriptome analysis of fasudil treatment in the APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer’s disease

The Effects of Alda-1 Treatment on Renal and Intestinal Injuries After Cardiopulmonary Resuscitation in Pigs

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