The inhibition of ORMDL3 prevents Alzheimer's disease through ferroptosis by PERK/ATF4/HSPA5 pathway

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with high incidence and widespread attention. There is currently no clear clarification of the pathogenesis. However, ORMDL3 causes ferroptosis in AD, and the potential mechanisms remain unclear. So, this study explore the function of ORMDL3 on ferroptosis in AD and its potential regulatory mechanisms. APPswe/PS1dE9 mice and C57BL/6 mice were induced into the mice model. The murine microglial BV‐2 cells also were induced into the vitro model. In serum samples of AD patients, ORMDL3 mRNA expression levels were upregulated. The serum ORMDL3 levels expression was positively related to the ADL score or MoCA score in AD patients. The serum ORMDL3 expression level was positively related to MMSE score or Hcy levels in AD patients. The mRNA expression of ORMDL3 in the hippocampal tissue of the mice model of AD was upregulated at one, four and eight months. The protein expression of ORMDL3 was upregulated in the mice model of AD. ORMDL3 promoted Alzheimer's disease, and increased oxidative response and ferroptosis in a model of AD. PERK/ATF4/HSPA5 pathway is one important signal pathway for the effects of ORMDL3 in a model of AD. Collectively, these data suggested that ORMDL3 promoted oxidative response and ferroptosis in a model of AD by the PERK/ATF4/HSPA5 pathway, which might be a novel target spot mechanism of ferroptosis in AD and may serve as a regulator of AD‐induced ferroptosis.

IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis

“…These results suggest that in our experimental systems these two ferroptosis-inducing agents do not activate the UPR. Although both the PERK-eIF2α-ATF4 and ATF6 branches of the UPR have been implicated in the regulation of ferroptosis with diverse cellular context and inducing agents [48][49][50][51][52][53][54][55][56][57][58][59][60] , we found that when the expression of the key transcription factors of the three UPR branches, XBP1, ATF4 and ATF6 was inhibited individually in MDA-MB-231 cells, ferroptosis induction by erastin treatment was not affected (Fig. 2B-D).…”

GPNMB+ microglia moderate the amyloid beta-tau interaction in early Alzheimer’s disease

“…HSPA5, a marker of ER stress associated with AD, 41,42 has been shown to interact in vitro with Aβ and tau, mitigating their toxicity. [43][44][45][46][47] Although in vivo studies have identified it as a candidate therapeutic target 48,49 , the detailed mechanisms of action and its relevance in the Aβ-tau interaction are not fully understood. 50…”

Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes

“…[ 176 ] ORMDL3 gene, a susceptibility gene closely related to the occurrence of childhood asthma, promote AD through inducing ferroptosis by PERK/ATF4/HSPA5 signaling pathway. [ 177 ]…”

“…[176] ORMDL3 gene, a susceptibility gene closely related to the occurrence of childhood asthma, promote AD through inducing ferroptosis by PERK/ATF4/HSPA5 signaling pathway. [177] The Role of LPO in AD: The mammalian brain is inadequately equipped with antioxidant defense systems and is prone to oxidative damage due to its high O 2 consumption, and neuronal membrane lipids rich in high PUFAs side-chains, especially DHA (C22:6) residues, [178] Iron is found throughout the brain, [28,179,180] neuronal mitochondria generate O 2…”