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Altered expression of diabetes-related genes in Alzheimer's disease brains: the Hisayama study.

Hokama M, Oka S, Leon J, Ninomiya T, Honda H, Sasaki K, Iwaki T, Ohara T, Sasaki T, LaFerla FM, Kiyohara Y, Nakabeppu Y - Cereb. Cortex (2013)

Bottom Line: Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting.Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD.These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Department of Neurosurgery, Graduate School of Medical Sciences.

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Top 3 networks of genes whose expression was significantly altered in the AD hippocampus. Among the top 200 transcription clusters shown in Supplementary Table S6, 145 genes were eligible for generating networks excluding microRNA–mRNA interactions by IPA. (A) Network 1 includes 16 downregulated genes (MET, PCSK1, PTPN3, SERPINF1, VEGFA, NEFH, EGR3, HOMER1, INA, DAGLA, CDH22, NEFL, TOM1L1, TOLLIP, SH3RF1, TOMM22), and 4 upregulated genes (AEBP1, TXNIP, VCAM1, ANGPT1). (B) Network 2 consists of 23 downregulated genes (RGS4, GABRA1, GFRA2, CPLX1, KCNK9, RGS7, ARHGDIG, GABRG2, STMN2, L1CAM, SYT7, SYT5, GABRA4, KCNJ6, STX1B, GABRA5, SNAP25, PTPRN, SYT4, DUSP6, SYN1, PTPN5, PTPRN2). (C) Network 3 consists of 13 downregulated genes (IL12RB2, PRKCB, WIPF3, NRN1, ENC1, SATB1, PHACTR1, ELAVL4, FABP3, AACS, LARGE, SPTBN2, YWHAG). Solid lines indicate direct interactions and dashed lines indicate indirect interactions. Downregulated molecules are shown in green and upregulated ones are shown in red. Encoded molecules were placed in an appropriate subcellular compartment based on IPA, if known. We added PCSK2 into Network 1, insulin, PCSK1, and PCSK2 into Network 2, and PCSK1 and PCSK2 into Network 3. PCSK1 and PCKS2 are known to be localized in secretary granules in the cytoplasm, but some amount of these proteins may be secreted into the extracellular space.
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BHT101F3: Top 3 networks of genes whose expression was significantly altered in the AD hippocampus. Among the top 200 transcription clusters shown in Supplementary Table S6, 145 genes were eligible for generating networks excluding microRNA–mRNA interactions by IPA. (A) Network 1 includes 16 downregulated genes (MET, PCSK1, PTPN3, SERPINF1, VEGFA, NEFH, EGR3, HOMER1, INA, DAGLA, CDH22, NEFL, TOM1L1, TOLLIP, SH3RF1, TOMM22), and 4 upregulated genes (AEBP1, TXNIP, VCAM1, ANGPT1). (B) Network 2 consists of 23 downregulated genes (RGS4, GABRA1, GFRA2, CPLX1, KCNK9, RGS7, ARHGDIG, GABRG2, STMN2, L1CAM, SYT7, SYT5, GABRA4, KCNJ6, STX1B, GABRA5, SNAP25, PTPRN, SYT4, DUSP6, SYN1, PTPN5, PTPRN2). (C) Network 3 consists of 13 downregulated genes (IL12RB2, PRKCB, WIPF3, NRN1, ENC1, SATB1, PHACTR1, ELAVL4, FABP3, AACS, LARGE, SPTBN2, YWHAG). Solid lines indicate direct interactions and dashed lines indicate indirect interactions. Downregulated molecules are shown in green and upregulated ones are shown in red. Encoded molecules were placed in an appropriate subcellular compartment based on IPA, if known. We added PCSK2 into Network 1, insulin, PCSK1, and PCSK2 into Network 2, and PCSK1 and PCSK2 into Network 3. PCSK1 and PCKS2 are known to be localized in secretary granules in the cytoplasm, but some amount of these proteins may be secreted into the extracellular space.

Mentions: Among the top 200 transcription clusters, 145 genes were eligible for generating IPA networks. The most relevant network included downregulated genes such as MET, PCSK1, PTPN3, SERPINF1, and VEGFA, and upregulated genes such as AEBP1 and TXNIP (Fig. 3A; Network 1). The second-most relevant network consisted of the genes encoding GABA receptors (GABRA1, GABRA4, GABRA5, GABRG2), synaptotagmin members, syntaxin, potassium channels, and regulators of G protein signaling. Expression of all of these genes was markedly decreased in the AD hippocampus (Fig. 3B; Network 2), reflecting the neuronal dysfunction in AD brain. The third-most relevant network consisted of genes regulated by insulin signaling pathways, as discussed below (Fig. 3C; Network 3). The alterations in the expression levels of the genes constituting these 3 networks were well preserved in the temporal cortex and to a lesser extent in the frontal cortex of AD brains (see Supplementary Table S6).Figure 3.


Altered expression of diabetes-related genes in Alzheimer's disease brains: the Hisayama study.

Hokama M, Oka S, Leon J, Ninomiya T, Honda H, Sasaki K, Iwaki T, Ohara T, Sasaki T, LaFerla FM, Kiyohara Y, Nakabeppu Y - Cereb. Cortex (2013)

Top 3 networks of genes whose expression was significantly altered in the AD hippocampus. Among the top 200 transcription clusters shown in Supplementary Table S6, 145 genes were eligible for generating networks excluding microRNA–mRNA interactions by IPA. (A) Network 1 includes 16 downregulated genes (MET, PCSK1, PTPN3, SERPINF1, VEGFA, NEFH, EGR3, HOMER1, INA, DAGLA, CDH22, NEFL, TOM1L1, TOLLIP, SH3RF1, TOMM22), and 4 upregulated genes (AEBP1, TXNIP, VCAM1, ANGPT1). (B) Network 2 consists of 23 downregulated genes (RGS4, GABRA1, GFRA2, CPLX1, KCNK9, RGS7, ARHGDIG, GABRG2, STMN2, L1CAM, SYT7, SYT5, GABRA4, KCNJ6, STX1B, GABRA5, SNAP25, PTPRN, SYT4, DUSP6, SYN1, PTPN5, PTPRN2). (C) Network 3 consists of 13 downregulated genes (IL12RB2, PRKCB, WIPF3, NRN1, ENC1, SATB1, PHACTR1, ELAVL4, FABP3, AACS, LARGE, SPTBN2, YWHAG). Solid lines indicate direct interactions and dashed lines indicate indirect interactions. Downregulated molecules are shown in green and upregulated ones are shown in red. Encoded molecules were placed in an appropriate subcellular compartment based on IPA, if known. We added PCSK2 into Network 1, insulin, PCSK1, and PCSK2 into Network 2, and PCSK1 and PCSK2 into Network 3. PCSK1 and PCKS2 are known to be localized in secretary granules in the cytoplasm, but some amount of these proteins may be secreted into the extracellular space.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128707&req=5

BHT101F3: Top 3 networks of genes whose expression was significantly altered in the AD hippocampus. Among the top 200 transcription clusters shown in Supplementary Table S6, 145 genes were eligible for generating networks excluding microRNA–mRNA interactions by IPA. (A) Network 1 includes 16 downregulated genes (MET, PCSK1, PTPN3, SERPINF1, VEGFA, NEFH, EGR3, HOMER1, INA, DAGLA, CDH22, NEFL, TOM1L1, TOLLIP, SH3RF1, TOMM22), and 4 upregulated genes (AEBP1, TXNIP, VCAM1, ANGPT1). (B) Network 2 consists of 23 downregulated genes (RGS4, GABRA1, GFRA2, CPLX1, KCNK9, RGS7, ARHGDIG, GABRG2, STMN2, L1CAM, SYT7, SYT5, GABRA4, KCNJ6, STX1B, GABRA5, SNAP25, PTPRN, SYT4, DUSP6, SYN1, PTPN5, PTPRN2). (C) Network 3 consists of 13 downregulated genes (IL12RB2, PRKCB, WIPF3, NRN1, ENC1, SATB1, PHACTR1, ELAVL4, FABP3, AACS, LARGE, SPTBN2, YWHAG). Solid lines indicate direct interactions and dashed lines indicate indirect interactions. Downregulated molecules are shown in green and upregulated ones are shown in red. Encoded molecules were placed in an appropriate subcellular compartment based on IPA, if known. We added PCSK2 into Network 1, insulin, PCSK1, and PCSK2 into Network 2, and PCSK1 and PCSK2 into Network 3. PCSK1 and PCKS2 are known to be localized in secretary granules in the cytoplasm, but some amount of these proteins may be secreted into the extracellular space.
Mentions: Among the top 200 transcription clusters, 145 genes were eligible for generating IPA networks. The most relevant network included downregulated genes such as MET, PCSK1, PTPN3, SERPINF1, and VEGFA, and upregulated genes such as AEBP1 and TXNIP (Fig. 3A; Network 1). The second-most relevant network consisted of the genes encoding GABA receptors (GABRA1, GABRA4, GABRA5, GABRG2), synaptotagmin members, syntaxin, potassium channels, and regulators of G protein signaling. Expression of all of these genes was markedly decreased in the AD hippocampus (Fig. 3B; Network 2), reflecting the neuronal dysfunction in AD brain. The third-most relevant network consisted of genes regulated by insulin signaling pathways, as discussed below (Fig. 3C; Network 3). The alterations in the expression levels of the genes constituting these 3 networks were well preserved in the temporal cortex and to a lesser extent in the frontal cortex of AD brains (see Supplementary Table S6).Figure 3.

Bottom Line: Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting.Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD.These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Department of Neurosurgery, Graduate School of Medical Sciences.

Show MeSH
Related in: MedlinePlus