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• Research Paper Volume 11, Issue 22 pp 10242-10251

  Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice

  Relevance score: 7.0794907

  Lizhi Chen, Shicheng Xu, Tong Wu, Yijia Shao, Li Luo, Lingqi Zhou, Shanshan Ou, Hai Tang, Wenhua Huang, Kaihua Guo, Jie Xu

  Keywords: mitochondria dysfunction, adenosine 5’-triphosphate, Amyloid-beta, platelets, APP/PS1 mice

  Published in Aging on November 19, 2019

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  The aging brain with mitochondrial dysfunction and a reduced adenosine 5’-triphosphate (ATP) has been implicated in the onset and progression of β-Amyloid (Aβ)-induced neuronal toxicity in AD. To unravel the function of ATP and the underlying mechanisms on AD development, APP/PS1 double transgenic mice and wild-type (WT) C57 mice at 6 and 10 months of age were studied. We demonstrated a decreased ATP release in the hippocampus and platelet of APP/PS1 mice, comparing to C57 mice at a relatively early age. Levels of Aβ were raised in both hippocampus and platelet of APP/PS1 mice, accompanied by a decrease of α-secretase activity and an increase of β-secretase activity. Moreover, our results presented an age-dependent rise in mitochondrial vulnerability to oxidation in APP/PS1 mice. In addition, we found decreased pSer473-Akt levels, increased GSK3β activity by inhibiting phosphorylation at Ser9 in aged APP/PS1 mice and these dysfunctions probably due to down-regulation of Bcl-2 and up-regulation of cleaved caspase-3. Therefore, we demonstrate that PI3K/Akt/GSK3β signaling pathway could be involved in Aβ-associated mitochondrial dysfunction of APP/PS1 mice and APP abnormal metabolism in platelet might provide potential biomarkers for early diagnosis of AD.

  

  Hippocampal and platelets ATP content in and from APP/PS1 transgenic mice and C57 mice. (A) ATP content in hippocampi; (B) ATP content in platelets. Results are expressed as a mean ± SD value of six experiments measured in duplicate. The values are expressed as percentage of control, which is set to 100%. ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Aβ1-40 and Aβ1-42 levels in hippocampus and platelets from APP/PS1 transgenic mice and C57 mice. (A) Aβ1-40 levels in hippocampus; (B) Aβ1-42 levels in hippocampus; (C) Aβ1-40 levels in platelets; (D) Aβ1-42 levels in platelets. Values are expressed as mean ± SD of six experiments measured in duplicate. ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Scatter plots of the correlation between hippocampal and platelet Aβ variables in APP/PS1 transgenic mice and C57 mice. (A) The correlation analysis between hippocampal Aβ1-40 and platelet Aβ1-40 at 6 and 10 months. (B) The correlation analysis between hippocampal Aβ1-42 and platelet Aβ1-42 at 6 and 10months.

  
  
  

  

  Activities of α- (A) and β-secretase (B) in platelets of APP/PS1 transgenic mice and C57 mice. ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Western blot analysis for p-Akt, p-GSK3β, Bcl-2 and Cleaved caspase-3 in the platelets of APP/PS1 transgenic mice and C57 mice. Band intensities were quantified using Image J software. Each value was calculated on the basis of the data obtained from three independent experiment. Representative bar diagram showing quantitative results for relative levels of (B) p-Akt, (C) p-GSK3β, (D) Bcl-2, (E) Cleaved caspase-3. ^*P < 0.05 vs. C57 (6 months), ^**P < 0.01 vs. C57 (6 months), ^##P < 0.01 vs. APP/PS1 (6 months), ⁺P < 0.05 vs. C57 (10 months), ⁺⁺P < 0.01 vs. C57 (10 months).

  
  
  

  

  Schematic representation of the potential mechanisms involved in Aβ-associated mitochondrial dysfunction in APP/PS1 mice. In the presence of Aβ, mitochondrial dysfunction has been shown to be associated with mitochondrial ATP production and cell signaling cascades, eventually leading to apoptosis. The red and blue arrows visualize the increased or decreased processes of APP/PS1 mice proteins compared to the control C57 mice, respectively.

  
  
  

  

  Research protocol. (A) An overview of the experimental scheme. (B) Graphic illustrating the platelet preparation from the tube-method protocol. The extraction of a small volume of whole blood (WB) was obtained from SAM-mice. After the single centrifugation at 150g for 20min, blood was fractionated into two layers: the bottom layer consists of red blood cells (RBC), and the top layer contains platelet rich plasma (PRP). The separated PRP was then centrifuged at 400g for 15min: the bottom consists of platelet pellets (PLT), and the top contains platelet poor plasma (PPP).

  
  
  

• Research Paper Volume 11, Issue 14 pp 5108-5123

  Activation of AK005401 aggravates acute ischemia/reperfusion mediated hippocampal injury by directly targeting YY1/FGF21

  Relevance score: 7.623025

  Hongzhi Wan, Ying Yang, Miao Li, Xin Liu, Yeying Sun, Kexin Wang, Chunxiang Zhang, Qingyin Zheng, Chaoyun Wang

  Keywords: Ak005401, ischemia/reperfusion, antioxidant capacity, mitochondria dysfunction, fibroblast growth factor 21

  Published in Aging on July 23, 2019

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  Ischemia exerts a negative impact on mitochondrial function, which ultimately results in neuronal damage via alterations in gene transcription and protein expression. Long non- coding RNAs (LncRNAs) play pivotal roles in the regulation of target protein expression and gene transcription. In the present study, we observed the effect of an unclassical LncRNA AK005401on ischemia/reperfusion (I/R) ischemia-mediated hippocampal injury and investigated the regulatory role of fibroblast growth factor 21 (FGF21) and Yin Yang 1 (YY1). C57Black/6 mice were subjected to I/R using the bilateral common carotid clip reperfusion method, and AK005401 siRNA oligos were administered via intracerebroventricular injection. HT22 cells were used to establish a model of oxygen-glucose deprivation/reoxygenation (OGD/R). We observed pathological morphology and mitochondrial structure. Neuronal apoptosis was evident. Cell activity, cell respiration, FGF21, YY1, and antioxidant capacity were evaluated. I/R or OGD/R significantly increased the expressions of AK005401and YY1 and decreased FGF21expression, which further attenuated the activation of PI3K/Akt, promoted reactive oxygen species (ROS) generation, and then caused mitochondria dysfunction and cell apoptosis, which were reversed by AK005401 siRNA oligos and were aggravated by overexpression of AK005401 and YY1. We conclude that AK005401/YY1/FGF21 signaling pathway has an important role in I/R-mediated hippocampal injury.

  

  Sequence site and possible relationships of AK005401, FGF21 and YY1. AK005401 is 1392 bp non-coding RNA sequence, which derived from the gene sequence (from 108329474 to 108330865) located on chromosome 12. FGF21 is 947 bp including three exon sequences (from 45,613,890 to 45,615,490) located on chromosome 7. YY1 located on chromosome 12 as like as AK005401 is from 108,793,311 to 108,816,632.

  
  
  

  

  Effect of AK005401on ischemia/reperfusion (I/R) induced mice hippocampus pathomorphology and motor score. The mice were divided into four groups: sham, I/R, AKsiRNA, and NC. In addition, AK005401 overexpression vector group and NC vector group were added. After reperfusion for 24 hours, the motor score of each mouse was obtained according to the neurological test method. The brains were fixed, embedded in paraffin, cut into 4-μm-thick sections, and stained with HE, cresyl violet and FJB. (A) The neurons in the CA1 hippocampus stained with HE were observed by light microscopy. Light microscopy shows normal neuronal cells (black solid line arrows), pathological neurons with shrunken cytoplasm, damaged nuclei (red solid line arrows), and vacuolization (blue solid line arrows). (B) Total motor scores in all groups were showed (n = 15). (C) The neurons stained with cresyl violet were observed by light microscopy. (D) The neurons stained with FJB were observed by light microscopy. (E) The percentage of cell deaths was analyzed (n=3). (F) F-JB⁺ cells were counted (n=3). Data were presented as mean±SD. One-way ANOVA test was used to determine statistical significance. **P < 0.01 vs. sham group, ^#P < 0.05 vs. I/R group.

  
  
  

  

  Effect of AK005401 on cell viability and apoptosis. HT22 cells were divided in four groups: control, OGD/R, AK005401siRNA, and NC. Cell viability was detected by MTT method. Cell apoptosis of all groups was observed by applying TUNEL apoptosis assay kit and AnnexinV/PI apoptosis assay kit, respectively. (A) apoptotic cells were visualized by TUNEL staining (red). Nuclei were counterstained with 4′,6-diamidino-2-phenylindole (DAPI, blue). (B) TUNEL positive apoptotic cells were counted as a percentage of the total number of cells. (C) Cell activities were evaluated using AnnexinV/PI apoptosis assay kit. (D) Apoptotic cells obtained from AnnexinV/PI method were counted as a percentage of the total number of cells. (E) Cell viabilities of all groups were measured by using MTT methods. Data were presented as mean±SD (n = 3 for apoptosis, n = 10 for cell viability). One-way ANOVA test was used to determine statistical significance. **P < 0.01 vs. control group, ^##P < 0.01 vs. OGD/R group.

  
  
  

  

  Effect of overexpression of AK005401and YY1 on cell viability and apoptosis and effect of AK005401 on ROS generation. Mice and HT22 cells were used to establish I/R model and OGD/R model, respectively. Cells were collected and seeded in a 96-well plate or 6-well plate and divided into seven groups as follows: control, OGD/R, OGD/R+AK005401 (OGD/R+ AK005401 overexpression vector), OGD/R+YY1 siRNA (OGD/R + AK005401 overexpression vector +YY1 siRNA), OGD/R+YY1 (OGD/R+ YY1 overexpression vector), OGD/R+FGF21 (OGD/R + YY1 overexpression vector +FGF21 overexpression vector) and OGD/R+NC vector(OGD/R+ negative control vector) groups. (A) Cell activities were evaluated using AnnexinV/PI apoptosis assay kit. (B) Apoptotic cells obtained from AnnexinV/PI method were counted as a percentage of the total number of cells. (C) Cell viability was detected by MTT method. ROS levels in all groups were detected using fluorescent microscope and flow cytometry. (D) ROS levels were observed using fluorescent microscope after treatment with DCFH-DA. (E) ROS production was analyzed by applying flow cytometry. (F) Effects of AK005401 on ROS levels in HT22 cells (n = 3 experiments). (G) the ROS contents in hippocampus tissues were measured at 450 nm according to the procedures described by ROS ELISA assay kits. Data were presented as mean±SD (n = 10 in hippocampus tissues, or n = 3 in cells). One-way ANOVA test was used to determine statistical significance. **P < 0.01 vs. sham group or control group, #P < 0.05 or ##P < 0.01 vs. I/R group or OGD/R group, ΔP < 0.05 or ΔΔP < 0.01 vs.OGD/R+AK005401 group, +P < 0.05 vs.OGD/R+YY1 group.

  
  
  

  

  Effect of AK005401 on antioxidant capacity and target genes expressions. Mice and HT22 cells were used to establish I/R model and OGD/R model, respectively. The activities of CuZn SOD and GSH-Px and MDA level in tissue and cells were determined with spectrophotometrical method according to the procedure described by assay kit. (A1–A3) represent the activities of SOD and GSH-Px and MDA level in hippocampus tissue (n=10). (B1–B3) represent the activities of SOD and GSH-Px and MDA level in cells (n=8). Total RNA were isolated from vascular endotheliums and RAECs using Trizol (Invitrogen) according to the manufacturer’s instruction. cDNA was synthesized with PrimeScript reverse transcriptase (TaKaRa, Dalian, China) and oligo (dT) (20 bp) following the manufacturer’s instructions. Real-time PCR was performed using SYBR Premix Ex TaqTM II kit. Relative expressions of AK005401, YY1, FGF21, and CuZn SOD were calculated using the 2^−ΔΔCT method on a real-time PCR system. (C1–C4) represent the expression levels of AK005401, YY1, FGF21, and CuZn SOD in hippocampus tissue, respectively. (D1–D4) represent the expression levels of AK005401, YY1, FGF21, and CuZn SOD in HT22 cells, respectively. Data were presented as mean±SD (n = 3). One-way ANOVA test was used to determine statistical significance. ^**P < 0.01 vs. normal group or control group, ^##P < 0.01 vs. I/R group or OGD/R group.

  
  
  

  

  Effect of AK005401 on target proteins expressions. Mice and HT22 cells were used to establish I/R model and OGD/R model, respectively. The expression levels of YY1, FGF21, PI3K, Akt, caspase 3, Bcl-2, and Bax were visualized using chemiluminescence method. As shown in Figure 6, (A) represents Western blots in panel (1, 2, 3, and 4 represent sham, I/R, AK005401siRNA, and NC, respectively). (A1–A6) represent the relative expressions of YY1, FGF21, PI3K, Akt, caspase 3, and the relative ratio of Bax/Bcl-2 in hippocampus tissue, respectively. As shown in Figure 6-2, (B) represents Western blots in panel (1, 2, 3, and 4 represent control, OGD/R, AKsiRNA, and NC, respectively). (B1–B6) represent the relative expressions of YY1, FGF21, PI3K, Akt, caspase 3, and the relative ratio of Bax/Bcl-2 in HT22 cells, respectively. Data were presented as mean±SD (n = 3). One-way ANOVA test was used to determine statistical significance. ^*P < 0.05 or ^**P < 0.01 vs. sham group or control group, ^##P < 0.01 vs. I/R group or OGD/R group.

  
  
  

  

  Effect of overexpression of AK005401 and YY1 on the expressions of target genes and proteins and effect of AK005401 on mitochondrial structure and cell respiration. HT22 cells were seeded in 96-well and 6-well plates and divided in seven groups for expression of target genes and proteins (control, OGD/R, OGD/R+AK005401, OGD/R+YY1, OGD/R+YY1 siRNA, OGD/R+FGF21 and OGD/R+NC vector) or four groups for cell respiration (control, OGD/R, AK005401siRNA, and NC). A represents Western blots in panel (1, 2, 3, 4,5,6 and 7 represent control, OGD/R, OGD/R+AK005401, OGD/R+YY1, OGD/R+YY1 siRNA, OGD/R+FGF21 and OGD/R+NC vector, respectively). (A1–A3) represent the relative expressions of YY1, FGF21and the relative ratio of Bax/Bcl-2 in cells, respectively. (B1–B3) represent represent the expression levels of AK005401, YY1 and FGF21 in HT22 cells, respectively. (C1–C4) represent mitochondria structure of control group, OGD/R group, AK005401siRNA group, and NC group, respectively, by using a transmission electron microscope (×20,000 magnification). Transmission electron microscope shows normal mitochondrial structure (red solid line arrows) and pathological mitochondria with irregular shape, as well as swollen (blue solid line arrow) and vesicular mitochondrial clusters (yellow solid line arrow). (D) represents mitochondrial oxygen consumption rate (OCR) of different groups. OCR was measured using an Oxygraph-2k system (n = 3 experiments per condition). Data were presented as mean±SD (n = 3). One-way ANOVA test was used to determine statistical significance. ^**P < 0.01 vs. control group, ^#P < 0.05 or ^##P < 0.01 vs. OGD/R group, ^ΔP < 0.05 or ^ΔΔP < 0.01 vs.OGD/R+AK005401 group, ⁺P < 0.05 or ⁺⁺P < 0.01 vs.OGD/R+YY1 group

  
  
  

• Editorial Volume 10, Issue 3 pp 295-296

  SIRT2 in age-related neurodegenerative disorders

  Relevance score: 9.449875

  Stéphane Fourcade, Tiago F. Outeiro, Aurora Pujol

  Keywords: sirtuins, SIRT2, neurodegeneration, mitochondria dysfunction

  Published in Aging on March 3, 2018

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• Research Paper Volume 7, Issue 8 pp 579-594

  Oxidative stress and ROS metabolism via down-regulation of sirtuin 3 expression in Cmah-null mice affect hearing loss

  Relevance score: 7.040536

  Deug-Nam Kwon, Woo-Jin Park, Yun-Jung Choi, Sangiliyandi Gurunathan, Jin-Hoi Kim

  Keywords: hearing loss, CMP-N-acetylneuraminic acid hydroxylase, ROS metabolism, mitochondria dysfunction, oxidative stress

  Published in Aging on August 29, 2015

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  CMP-Neu5Ac hydroxylase (Cmah) disruption caused several abnormalities and diseases including hearing loss in old age. However, underling molecular mechanisms that give rise to age-related hearing loss (AHL) in Cmah-null mouse are still obscure. In this study, Cmah-null mice showed age-related decline of hearing associated with loss of sensory hair cells, spiral ganglion neurons, and/or stria vascularis degeneration in the cochlea. To identify differential gene expression profiles and pathway associated with AHL, we performed microarray analysis using Illumina MouseRef-8 v2 Expression BeadChip and pathway-focused PCR array in the cochlear tissues of Cmah-null mouse. Pathway and molecular mechanism analysis using differentially expressed genes provided evidences that altered biological pathway due to oxidative damage by low expressed antioxidants and dysregulated reactive oxygen species (ROS) metabolism. Especially, low sirtuin 3 (Sirt3) gene expressions in Cmah-null mice decreased both of downstream regulator (Foxo1 and MnSod) and regulatory transcription factor (Hif1α and Foxo3a) gene expression. Taken together, we suggest that down-regulation of Sirt3 expression leads to oxidative stress and mitochondrial dysfunction by regulation of ROS and that it could alter various signaling pathways in Cmah-null mice with AHL

  

  (A) Analysis of Neu5Gc expression in cochlear tissues of WT- and Cmah-null mice by IHC using a chicken anti-Neu5Gc antibody. (B) Histological abnormality in inner ears of Cmah-null mice. Deposition of unusual and apparently a cellular material in the vestibular otoconial epithelia (upper). The area of the outer hair cells showed degeneration of the sensory cells throughout the cochlea in the cochlear sensory epithelium, (bottom). SV: scala vestibule, SM: scala media, ST: scala tympani, SG: spiral ganglion, BM: sasilar membrane, RM: reissner's membrane, Sv: stria vascularis, OT: otoconia, OM: otolithic membrane, NHC & SC: neuroepithelial hair cells and supporting cells, HC: hair cells, OHCs: outer hair cells, SL: Spiral lamina. (C) Apoptotic cell death in the cochlea of Cmah-null mice. TUNEL labeling performed on paraffin sections the cochlea from WT- and Cmah-null mice. (D) The expression of ganglion cells in cochlear tissues from WT- and Cmah-null mice by IHC. Rectangular box indicate a higher magnification images (5x) in left panel. GFAP: Glial fibrillary acidic protein, NSE: Neuron specific enolase, NF: Neurofilament, VIM: Vimentin. SL: spiral lamina, OC: organ of corti, SG: spiral ganglion. (E) mRNA expression pattern of neuronal cell markers in cochlear tissues from WT- and Cmah-null mice. RT-qPCR was used to measure the expression of Gfap, Nse, Nf, and Vim in the cochlea from WT- and Cmah-null mice.

  
  
  

  

  (A) Scatterplot of normalized mRNA expression by microarray. Data are log2 normalized. Grey- and orange-spots indicate no significant genes and up- or down-regulated genes, with more than 1.5-fold change. (B) Venn diagram showing differential expression of genes in the cochlear tissues of Cmah-null mice. Numbers in red and blue Venn diagram present up- and down-regulated genes, respectively. (C) The differentially up- or down-regulated genes were clarified according to biological process, molecular function, and cellular component. GO classification significantly enriched with a Benjamini-Hochberg corrected P value < 0.05 among all differentially expressed genes with ≥ 1.5-fold expression between WT- and Cmah-null mice.

  
  
  

  

  (A) Pie chart analysis of the disease or functions annotation for neurological disease. (B) The network of canonical pathways highlights the relationships between pathways and classifies the functional groups by IPA analysis. Group I and II represent oxidative stress and mitochondrial dysfunction-related signaling (Group I), and Wnt/β-catenin signaling (Group II), respectively.

  
  
  

  

  (A) IHC in cochlea of WT- and Cmah-null mouse for detection of Sirt3. Bar: 200 um. SV: scala vestibule, RM: reissner's membrane, SM: scala media, ST: scala tympani, Sv: stria vascularis, SL: spiral lamina. (B) Expression levels of sirtuins were determined by RT-qPCR of RNA samples from cochlear tissues of WT- and Cmah-null mice. (C) Expression of AHL related genes on the microarray data from cochlear tissues of Cmah-null mice. (D) Expression levels of genes involved in the regulatory factor of sirtuin, Wnt signaling, and mitochondrial functional regulation were determined by RT-qPCR of RNA samples from cochlear tissues of WT- and Cmah-null mice. (E) Measurement of mitochondrial activity in the cochlea of WT- and Cmah-null mice. Immunofluorescence was performed using a mitochondrial marker antibody. The intensity of the fluorescent signal indicates mitochondria numbers or the level of integrity. (F) Summary model describing the molecular mechanisms for sirtuins and oxidative stress regulation, Wnt signaling, and mitochondrial dysfunction by identified RT-qPCR results and array date set. The down-regulated Sirt3 lead to oxidative damage and mitochondrial dysfunction and could be alter various signaling pathways in Cmah-null mice with AHL. Sirt3-5: NAD-dependent protein deacetylase sirtuin3-5, Hif1α: Hypoxia-inducible factor 1-alpha, Foxo3a: Forkhead box O3, Foxo1: Forkhead box protein O1, MnSod: superoxide dismutase 2, mitochondrial, Lrp5-6: Low-density lipoprotein receptor-related protein 5-6, Wnt: Wingless, the Drosophila melanogaster segment-polarity gene, and Integrase-1 the vertebrate homologue, Gsk3β: Glycogen synthase kinase 3 beta, Cbr1: carbonyl reductase 1, Imp1: inner mitochondrial membrane peptidase-like, Mtfp1: mitochondrial fission process 1, RhoT2: Mitochondrial Rho GTPase 2, CytoC: Cytochrome C, Soc1-2: soluble oxidase component 1-2.