NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases

Over-expression of NOX4 increases impairment of mitochondrial metabolism in human astrocytes.

“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”

• Also stated in: § Introduction · plain

  “We found that the elevation of NOX4 promotes the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production in human astrocytes.”

MDA levels are elevated in impaired astrocytes of mouse AD.

“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”

• Also stated in: § Introduction · plain

  “The levels of 4-HNE and MDA were also significantly elevated in impaired astrocytes of patients with AD and mouse AD.”

4-HNE levels are elevated in impaired astrocytes of patients with AD.

“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”

• Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · hedged

  “These results suggest that the levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of patients with AD.”

• Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · plain

  “The levels of 4-HNE and MDA were generally higher in every individual patient with AD.”

Over-expression of NOX4 reduces five protein complexes in the mitochondrial ETC in human astrocytes.

“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”

Elevation of NOX4 induces mitochondrial fragmentation in human astrocytes.

“Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes.”

• Also stated in: § Introduction · plain

  “The elevation of NOX4 induced mtROS production and mitochondrial fragmentation in human astrocytes.”

NOX4 protein levels are elevated in impaired astrocytes of cerebral cortex from APP/PS1 double-transgenic mouse model of AD.

“Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD.”

• Also stated in: § Introduction · plain

  “Here, our results showed that the levels of NOX4 were significantly elevated in impaired astrocytes in patients with AD and APP/PS1 double-transgenic mouse model of AD.”

Elevation of NOX4 induces mtROS production in human astrocytes.

“Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes.”

• Also stated in: § Introduction · plain

  “The elevation of NOX4 induced mtROS production and mitochondrial fragmentation in human astrocytes.”

Elevation of NOX4 increases ferroptosis-dependent cytotoxicity in human astrocytes.

“Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes.”

• Also stated in: § Introduction · plain

  “Notably, the elevation of NOX4 induced ferroptosis-dependent cytotoxicity by the activation of lipid peroxidation in human astrocytes.”

4-HNE levels are elevated in impaired astrocytes of mouse AD.

“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”

• Also stated in: § Introduction · plain

  “The levels of 4-HNE and MDA were also significantly elevated in impaired astrocytes of patients with AD and mouse AD.”

The number of impaired astrocytes with positive subcellular co-localization between NOX4 and GFAP is increased in patients with AD compared to non-AD donors.

“Notably, the number of impaired astrocytes which have the positive subcellular co-localization between NOX4 and GFAP was significantly increased in patients with AD (AD) (Fig. 1C).”

MDA levels are elevated in impaired astrocytes of patients with AD.

“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”

• Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · hedged

  “These results suggest that the levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of patients with AD.”

• Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · plain

  “The levels of 4-HNE and MDA were generally higher in every individual patient with AD.”

Elevation of NOX4 activates oxidative stress-induced lipid peroxidation in human astrocytes.

“Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes.”

• Also stated in: § Introduction · plain

  “Notably, the elevation of NOX4 induced ferroptosis-dependent cytotoxicity by the activation of lipid peroxidation in human astrocytes.”

The levels of NOX4 are generally higher in every individual patient with AD relative to non-AD donors.

“The levels of NOX4 were generally higher in every individual patient with AD relative to non-AD donor (Normal).”

NOX4 protein levels are elevated in impaired astrocytes of cerebral cortex from patients with AD.

“Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD.”

• Also stated in: § The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · hedged

  “These results suggest that the protein levels of NOX4 are elevated in impaired astrocytes of patients with AD.”

• Also stated in: § The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · plain

  “The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases”

Over-expression of NOX4 inhibits mitochondrial respiration in human astrocytes.

“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”

• Also stated in: § Introduction · plain

  “We found that the elevation of NOX4 promotes the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production in human astrocytes.”

Elevation of NOX4 inhibits cellular antioxidant process in human astrocytes.

“Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes.”

Over-expression of NOX4 inhibits ATP production in human astrocytes.

“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”

• Also stated in: § Introduction · plain

  “We found that the elevation of NOX4 promotes the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production in human astrocytes.”

NOX4 elevation increases MDA levels in human astrocytes compared to control.

“Moreover, the elevation of NOX4 increased the levels of MDA relative to control (Fig. 7C and Fig. S10).”

NOX4 elevation increases iron accumulation in human astrocytes compared to control.

“Notably, the elevation of NOX4 increased the accumulation of iron, a specific marker of ferroptosis, compared to control (Fig. 7D).”

NOX4 over-expression significantly suppresses basal OCR in human astrocytes compared to control.

“The basal levels of OCR were significantly suppressed by NOX4 over-expression relative to control (Fig. 5A and B).”

NOX4 elevation inhibits nuclear translocation of NRF2 from cytosol in human astrocytes compared to control.

“The elevation of NOX4 inhibited the nuclear translocation of NRF2 from cytosol compared to control (Fig. 6D and Fig. S9).”

The number of cells showing mitochondrial fragmentation is significantly increased by NOX4 over-expression in human astrocytes compared to control.

“The number of cells showing the fragmentation of mitochondria was significantly increased by NOX4 over-expression relative to control (Fig. 5G).”

NOX4 elevation increases 4-HNE levels in human astrocytes compared to control.

“Notably, immunofluorescence staining revealed that the elevation of NOX4 increased the levels of 4-HNE protein compared to control (Fig. 7A).”

• Also stated in: § NOX4 promotes ferroptosis by oxidative stress-induced lipid peroxidation in human astrocytes · plain

  “Moreover, the levels of 4-HNE were increased by NOX4 over-expression compared to control (Fig. 7C and S10).”

In cerebral cortex of patients with AD, 4-HNE co-localizes in NOX4-positive astrocytes.

“(D) Representative immunofluorescence images of 4-HNE protein expression in NOX4-positive astrocytes of patients with AD (AD) or non-AD (normal) showing 4-HNE (purple) in NOX4 (green)-positive astrocytes expressing astrocytes marker GFAP (red) around molecular layer (ML) (n = 10 images per individual subject).”

4-HNE expression is co-localized in NOX4-positive astrocytes of patients with AD relative to non-AD donors.

“Moreover, the expression of 4-HNE was co-localized in NOX4-positive astrocytes of patients with AD (AD) relative to non-AD donor (Normal) (Fig. 2D and Fig. S4).”

NOX4 over-expression significantly suppresses HO-1 activity in human astrocytes compared to control.

“Moreover, the levels and activity of heme oxygenase-1 (HO-1) (Fig. 6E and F) and glutamate cysteine ligase (GCL) (Fig. 6E and F) as target genes of NRF2 were significantly suppressed by NOX4 over-expression in human astrocytes.”

NOX4 over-expression significantly suppresses GCL activity in human astrocytes compared to control.

“Moreover, the levels and activity of heme oxygenase-1 (HO-1) (Fig. 6E and F) and glutamate cysteine ligase (GCL) (Fig. 6E and F) as target genes of NRF2 were significantly suppressed by NOX4 over-expression in human astrocytes.”

NOX4 over-expression significantly suppresses HO-1 protein levels in human astrocytes compared to control.

“Moreover, the levels and activity of heme oxygenase-1 (HO-1) (Fig. 6E and F) and glutamate cysteine ligase (GCL) (Fig. 6E and F) as target genes of NRF2 were significantly suppressed by NOX4 over-expression in human astrocytes.”

In cortex of APP/PS1 mice, the intensity of NOX4-positive staining in GFAP-positive astrocytes is increased compared to WT mice.

“Immunofluorescence staining revealed that the intensity of NOX4-positive staining in GFAP-positive astrocytes was increased in the cortex region of APP/PS1 mice compared to WT mice (Fig. 3A and B).”

NOX4 elevation significantly reduces the ratio of GSH to GSSG in human astrocytes compared to control.

“The elevation of NOX4 significantly reduced the levels of glutathione (GSH) and the ratio of GSH/oxidized glutathione (GSSG) relative to control (Fig. 6A and B).”

NOX4 elevation induces morphological features of cytotoxicity including shrinkage of cytosolic area and blebbing in human astrocytes compared to control.

“Consistent with the levels of 4-HNE, the elevation of NOX4 induced the morphological features of cytotoxicity including shrinkage of cytosolic area and blebbing relative to control (Fig. 7E).”

NOX4 elevation induces fragmentation of mitochondria in human astrocytes compared to control.

“Immunofluorescence staining revealed that elevation of NOX4 induced the fragmentation of mitochondria compared to control (Fig. 5F).”

In cortex of APP/PS1 mice, the number of impaired astrocytes with positive subcellular co-localization between MDA and GFAP is increased compared to WT mice.

“Similar with these results, the intensity of MDA-positive staining in GFAP-positive astrocytes (Fig. 4B and E and Fig. S6) and the number of impaired astrocytes which have the positive subcellular co-localization between MDA and GFAP (Fig. 4F) was increased in the cortex region of APP/PS1 mice compared to WT mice.”

The number of NOX4 and 4-HNE positive astrocytes is increased in patients with AD relative to non-AD donors.

“The number of NOX4 and 4-HNE positive astrocytes was significantly increased in patients with AD (AD) relative to non-AD donor (Normal) (Fig. 2E).”

The number of impaired astrocytes with positive subcellular co-localization between 4-HNE and GFAP is increased in patients with AD.

“Notably, the number of impaired astrocytes which have the positive subcellular co-localization between 4-HNE and GFAP was significantly increased in patients with AD (AD) (Fig. 2C).”

In cortex of APP/PS1 mice, 4-HNE is co-localized in NOX4-positive astrocytes compared to WT mice.

“Moreover, the expression of 4-HNE was co-localized in NOX4-positive astrocytes of APP/PS1 mice compared to WT mice (Fig. 4G and Fig. S7).”

NOX4 over-expression significantly reduces OCR levels in response to oligomycin and FCCP in human astrocytes compared to control.

“Moreover, the levels of OCR in response to oligomycin and FCCP were significantly reduced by NOX4 over-expression compared to control (Fig. 5A and B).”

In cerebral cortex of patients with AD, the number of NOX4 and 4-HNE positive astrocytes is higher than in non-AD controls.

“(E) Quantification of NOX4 and 4-HNE positive astrocytes from immunofluorescence images in the cerebral cortex region from patients with AD (AD) or non-AD (normal) (n = 10 images per individual subject). Data are mean ± standard deviation (SD). **, p < 0.01 by Student's two-tailed t-test.”

The number of impaired astrocytes with positive subcellular co-localization between MDA and GFAP is increased in patients with AD.

“the number of impaired astrocytes which have the positive subcellular co-localization between MDA and GFAP was increased in molecular layer (ML) of the cortex region of patients with AD (AD) relative to non-AD donor (Normal) (Fig. S3).”

In cerebral cortex of patients with AD, the intensity of 4-HNE-positive staining in astrocytes is higher than in non-AD controls.

“Quantification of intensity of 4-HNE positive staining in astrocytes from immunofluorescence images in the cerebral cortex region from patients with AD (AD #1, AD #2, AD #3) or non-AD (normal) (n = 3 per group, n = 10 images per individual subject). Data are mean ± standard deviation (SD). **, p < 0.01 by Student's two-tailed t-test.”

In cortex of APP/PS1 mice, the intensity of 4-HNE-positive staining is elevated in impaired GFAP-positive astrocytes.

“Moreover, the intensity of 4-HNE-positive staining was elevated in impaired GFAP-positive astrocytes in the cortex region of APP/PS1 mice.”

In cortex of APP/PS1 mice, the number of impaired astrocytes with positive subcellular co-localization between 4-HNE and GFAP is significantly increased compared to WT mice.

“Furthermore, the number of impaired astrocytes which have the positive subcellular co-localization between 4-HNE and GFAP was significantly increased in APP/PS1 mice relative to WT mice (Fig. 4D).”

NOX4 elevation significantly increases cytotoxicity levels in human astrocytes compared to control.

“Consistent with results of morphological analysis, the elevation of NOX4 significantly increased the levels of cytotoxicity relative to control (Fig. 7G).”

NOX4 over-expression significantly suppresses GCLC protein levels in human astrocytes compared to control.

“Moreover, the levels and activity of heme oxygenase-1 (HO-1) (Fig. 6E and F) and glutamate cysteine ligase (GCL) (Fig. 6E and F) as target genes of NRF2 were significantly suppressed by NOX4 over-expression in human astrocytes.”

In cortex of APP/PS1 mice, the intensity of 4-HNE-positive staining in GFAP-positive astrocytes is increased compared to WT mice.

“Immunofluorescence staining revealed that the intensity of 4-HNE-positive staining in GFAP-positive astrocytes was increased of the cortex region of APP/PS1 mice compared to WT mice (Fig. 4A and C and Fig. S6).”

In cortex of APP/PS1 mice, the intensity of MDA-positive staining in GFAP-positive astrocytes is increased compared to WT mice.

“Similar with these results, the intensity of MDA-positive staining in GFAP-positive astrocytes (Fig. 4B and E and Fig. S6) and the number of impaired astrocytes which have the positive subcellular co-localization between MDA and GFAP (Fig. 4F) was increased in the cortex region of APP/PS1 mice compared to WT mice.”

NOX4 over-expression significantly increases mtROS production in human astrocytes compared to control.

“Over-expression of NOX4 significantly increased the production of mtROS compared to control (Fig. 5E).”

NOX4 over-expression significantly reduces ATP production in human astrocytes compared to control.

“NOX4 over-expression significantly reduces the production of ATP relative to control (Fig. 5D).”

NOX4 over-expression significantly suppresses the protein levels of five mitochondrial oxidative phosphorylation enzyme complexes (NDUFB8, SDHB, UQCRC2, MTCO1, ATP5F1A) in human astrocytes compared to control.

“Consistent with the levels of OCR, over-expression of NOX4 significantly suppressed the protein levels of five mitochondrial oxidative phosphorylation enzyme complexes compared to control.”

In cortex of APP/PS1 mice, the number of NOX4 and 4-HNE positive astrocytes is significantly increased compared to WT mice.

“The number of NOX4 and 4-HNE positive astrocytes was significantly increased in APP/PS1 mice compared to WT mice (Fig. 4H).”

NOX4 elevation increases GSSG levels in human astrocytes compared to control.

“Also, the elevation of NOX4 increased the levels of GSSG compared to control (Fig. 6C).”

In cerebral cortex of patients with AD, the number of 4-HNE-positive astrocytes is higher than in non-AD controls.

“(C) Quantification of 4-HNE positive astrocytes from immunofluorescence images in the cerebral cortex region from patients with AD (AD #1, AD #2, AD #3) or non-AD (normal) (n = 3 per group, n = 10 images per individual subject). Data are mean ± standard deviation (SD). **, p < 0.01 by Student's two-tailed t-test.”

NOX4 over-expression increases the number of 4-HNE-positive cells in human astrocytes compared to control.

“The number of 4-HNE-positive cells was significantly increased by NOX4 over-expression relative to control (Fig. 7B).”

In cortex of APP/PS1 mice, the number of impaired astrocytes with positive subcellular co-localization between NOX4 and GFAP is significantly increased compared to WT mice.

“Moreover, the number of impaired astrocytes which have the positive subcellular co-localization between NOX4 and GFAP was significantly increased in APP/PS1 mice than in WT mice (Fig. 3C).”

NOX4 elevation significantly reduces GSH levels in human astrocytes compared to control.

“The elevation of NOX4 significantly reduced the levels of glutathione (GSH) and the ratio of GSH/oxidized glutathione (GSSG) relative to control (Fig. 6A and B).”

The number of morphological dead cells is significantly increased by NOX4 elevation in human astrocytes compared to control.

“Moreover, the number of morphological dead cells by NOX4 elevation was significantly increased compared to control (Fig. 7F).”

The elevation of NOX4 promotes ferroptosis by the accumulation of 4-HNE and morphological cytotoxicity.

“Our findings showed that the elevation of NOX4 promotes ferroptosis by the accumulation of 4-HNE and morphological cytotoxicity.”

Oxidative stress from mitochondrial dysfunction occurs in the early stage of AD.

“Oxidative stress from mitochondrial dysfunction occurs in the early stage of AD [7,8].”

• cites [7] Wang, 2014, Oxidative stress and mitochondrial dysfunction in Alzheimer's disease, Biochim. Biophys. Acta sourceNot checked yet

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• cites [8] Marcus, 1998, Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease, Exp. Neurol. sourceNot checked yet

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Impairment of astrocytes is elevated in brains of patients with AD.

“Previously, we have shown that the impairment of astrocytes is elevated in brains of patients with AD [23].”

• cites [23] Yoo, 2020, Elevated CLOCK and BMAL1 contribute to the impairment of aerobic glycolysis from astrocytes in Alzheimer's disease, Int. J. Mol. Sci. sourceNot checked yet

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NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via impairment of mitochondrial metabolism in AD.

“These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.”

• Also stated in: § Introduction · hedged

  “Our results suggest that NOX4 promotes ferroptosis of astrocytes by lipid peroxidation via the impairment of mitochondrial metabolism in AD.”

• AssumptionRests on an assumption: The mechanisms by which NOX4 regulates ferroptosis of astrocytes by oxidative stress via impairment of mitochondrial metabolism in AD remain unclear.

Elevated NOX4 promotes ferroptosis by oxidative stress-induced lipid peroxidation via impairment of mitochondrial function in Alzheimer's diseases.

“In summary, our results demonstrate that elevated NOX4 promotes ferroptosis by oxidative stress-induced lipid peroxidation via impairment of mitochondrial function in Alzheimer's diseases (Fig. 8).”

• AssumptionRests on an assumption: 4-HNE is a marker for ferroptosis.
• AssumptionRests on an assumption: Iron accumulation is a specific marker of ferroptosis.
• AssumptionRests on an assumption: NRF2 is a key regulator of the cellular antioxidant response.
• AssumptionRests on an assumption: HO-1 and GCL are target genes of NRF2.
• AssumptionRests on an assumption: Mitochondrial fragmentation indicates mitochondrial impairment.

The protein levels of NOX4 are elevated in impaired astrocytes of APP/PS1 mice.

“These results suggest that the protein levels of NOX4 are elevated in impaired astrocytes of APP/PS1 mice.”

The suppression of mitochondria-related oxygen metabolism has been identified in the frontal, parietal and temporal cortex in brains of patients with AD.

“The suppression of mitochondria-related oxygen metabolism has been identified in the frontal, parietal and temporal cortex in brains of patients with AD [[38], [39], [40]].”

• cites [38], [39], [40]Not checked yet

  Not checked in the free run.

The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of APP/PS1 mice.

“These results suggest that the levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of APP/PS1 mice.”

NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes.

“These results suggest that NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes.”

• AssumptionRests on an assumption: NRF2 is a key regulator of the cellular antioxidant response.
• AssumptionRests on an assumption: HO-1 and GCL are target genes of NRF2.

NOX4 could be an upstream molecular target in the impairment of mitochondrial oxygen metabolism by inhibition of mitochondrial respiration and ATP production in astrocytes during AD.

“Our results suggest that NOX4 could be an upstream molecular target in the impairment of mitochondrial oxygen metabolism by inhibition of mitochondrial respiration and ATP production in astrocytes during AD.”

• AssumptionRests on an assumption: Mitochondrial fragmentation indicates mitochondrial impairment.

The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes.

“These results suggest that the elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes.”

• AssumptionRests on an assumption: Mitochondrial fragmentation indicates mitochondrial impairment.

NOX4 promotes ferroptosis of astrocytes in AD.

“Here we demonstrate that NOX4 promotes ferroptosis of astrocytes in AD.”

• AssumptionRests on an assumption: 4-HNE is a marker for ferroptosis.
• AssumptionRests on an assumption: Iron accumulation is a specific marker of ferroptosis.

NOX4 might be critical for oxidative stress by ROS production in astrocytes during AD.

“Our findings suggest that NOX4 might be critical for oxidative stress by ROS production in astrocytes during AD.”

The expression of genes and proteins encoding subunits of the mitochondrial electron transport chain (ETC) in mitochondrial metabolic pathways was reduced in brain tissues of patients with AD.

“Also, the expression of genes and proteins encoding subunits of the mitochondrial electron transport chain (ETC) in mitochondrial metabolic pathways was reduced in brain tissues of patients with AD [41].”

• cites [41] Liang, 2008, Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons, Proc. Natl. Acad. Sci. U. S. A. sourceNot checked yet

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The elevation of NOX4 induces the impairment of mitochondrial metabolism and oxidative stress-induced lipid peroxidation in human astrocytes.

“We suggest that the elevation of NOX4 induces the impairment of mitochondrial metabolism and oxidative stress-induced lipid peroxidation in human astrocytes.”

• AssumptionRests on an assumption: NRF2 is a key regulator of the cellular antioxidant response.
• AssumptionRests on an assumption: HO-1 and GCL are target genes of NRF2.
• AssumptionRests on an assumption: Mitochondrial fragmentation indicates mitochondrial impairment.

The elevation of NOX4 is critical for ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in the pathogenesis of AD.

“Our findings provide a molecular mechanism by which the elevation of NOX4 is critical for ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in the pathogenesis of AD.”

• AssumptionRests on an assumption: 4-HNE is a marker for ferroptosis.
• AssumptionRests on an assumption: Iron accumulation is a specific marker of ferroptosis.
• AssumptionRests on an assumption: NRF2 is a key regulator of the cellular antioxidant response.
• AssumptionRests on an assumption: HO-1 and GCL are target genes of NRF2.
• AssumptionRests on an assumption: Mitochondrial fragmentation indicates mitochondrial impairment.

The elevation of NOX4 suppresses the mitochondrial respiration and ATP production rate via the reduction of five protein complexes in the mitochondrial ETC of human astrocytes.

“Our results showed that the elevation of NOX4 suppresses the mitochondrial respiration and ATP production rate via the reduction of five protein complexes in the mitochondrial ETC of human astrocytes.”

• AssumptionRests on an assumption: Mitochondrial fragmentation indicates mitochondrial impairment.

Astrocytes are associated with oxidative stress by Aβ-induced ROS production.

“Astrocytes are associated with oxidative stress by Aβ-induced ROS production [46].”

• cites [46] Abramov, 2004, Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase, J. Neurosci. sourceNot checked yet

  Not checked in the free run.

NOX4 promotes ferroptosis by oxidative stress-induced lipid peroxidation in human astrocytes.

“These results suggest that NOX4 promotes ferroptosis by oxidative stress-induced lipid peroxidation in human astrocytes.”

• AssumptionRests on an assumption: 4-HNE is a marker for ferroptosis.
• AssumptionRests on an assumption: Iron accumulation is a specific marker of ferroptosis.

Oxidative stress-induced lipid peroxidation levels are elevated in impaired astrocytes of patients with AD.

“These results suggest that the levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of patients with AD.”

• Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · plain

  “The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases”

The elevation of NOX4 protein levels in astrocytes of brains from patients with AD and APP/PS1 mice may represent a high activity of NOX4 in AD.

“In our results, the elevation of NOX4 protein levels in astrocytes of brains from patients with AD and APP/PS1 mice may represent a high activity of NOX4 in AD.”

• AssumptionRests on an assumption: APP/PS1 mice model AD.

The features of ferroptosis, such as iron dysregulation, lipid peroxidation, and inflammation, are important pathological events of Alzheimer's disease and cognitive dysfunction.

“The features of ferroptosis, such as iron dysregulation, lipid peroxidation and inflammation, are important pathological events of AD and cognitive dysfunction [52].”

• cites [52] Hambright, 2017, Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration, Redox Biol sourceNot checked yet

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The brain contains high levels of polyunsaturated fatty acids (PUFAs) in its membrane-rich architecture.

“the brain contains the high levels of polyunsaturated fatty acids (PUFAs) in its membrane rich architecture”

• cites [53] Coyle, 1993, Oxidative stress, glutamate, and neurodegenerative disorders, Science sourceNot checked yet

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• cites [54] Praticò, 2004, Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer's disease, J Alzheimers Dis sourceNot checked yet

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Lipid peroxidation could be a major feature of ferroptosis in Alzheimer's disease.

“lipid peroxidation could be a major feature of ferroptosis in AD”

• cites [53] Coyle, 1993, Oxidative stress, glutamate, and neurodegenerative disorders, Science sourceNot checked yet

  Not checked in the free run.

• cites [54] Praticò, 2004, Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer's disease, J Alzheimers Dis sourceNot checked yet

  Not checked in the free run.

NOX4 is an upstream molecular target of lipid peroxidation-derived ferroptosis in impaired astrocytes during Alzheimer's disease.

“Our results suggest that NOX4 is an upstream molecular target of lipid peroxidation-derived ferroptosis in impaired astrocytes during AD.”

The elevation of 4-HNE levels induces impairment of astrocytes in patients with Alzheimer's disease and human astrocytes.

“Consistent with previous studies, our results suggest that the elevation of 4-HNE levels induces impairment of astrocytes in patients with AD and human astrocytes.”

A high level of lipid peroxidation can disrupt cellular function as the driving force of ferroptosis.

“As the driving force of ferroptosis, a high level of lipid peroxidation can disrupt cellular function [56].”

• cites [56] Yang, 2016, Ferroptosis: death by lipid peroxidation, Trends Cell Biol. sourceNot checked yet

  Not checked in the free run.

NOX4-induced mitochondrial impairment and lipid peroxidation might be a critical pathway for neurodegeneration in Alzheimer's disease related to redox imbalance and oxidative stress.

“Consistent with previous studies, our results suggest that NOX4-induced mitochondrial impairment and lipid peroxidation might be a critical pathway for neurodegeneration in AD related to redox imbalance and oxidative stress.”

NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via impairment of mitochondrial metabolism as an important molecular mechanism in the impairment of astrocytes during Alzheimer's disease.

“In summary, our study demonstrates that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via impairment of mitochondrial metabolism as an important molecular mechanism in the impairment of astrocytes during AD.”