PubMed:18184791 JSONTXT

{"project":"test_HZAU_BioNLP","denotations":[{"id":"T1","span":{"begin":566,"end":571},"obj":"https://www.uniprot.org/uniprot/P49841"},{"id":"T2","span":{"begin":1136,"end":1141},"obj":"https://www.uniprot.org/uniprot/P49841"},{"id":"T3","span":{"begin":1430,"end":1435},"obj":"https://www.uniprot.org/uniprot/P49841"}],"text":"Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling.\nThe role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients."}

{"project":"PMID_GLOBAL","denotations":[{"id":"T1","span":{"begin":18,"end":21},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":908,"end":917},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":994,"end":1020},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":1022,"end":1025},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T5","span":{"begin":1407,"end":1410},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T6","span":{"begin":1614,"end":1617},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0100087"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0000605"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"0100087"},{"id":"A4","pred":"mondo_id","subj":"T4","obj":"0100087"},{"id":"A5","pred":"mondo_id","subj":"T5","obj":"0100087"},{"id":"A6","pred":"mondo_id","subj":"T6","obj":"0100087"}],"text":"Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling.\nThe role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients."}

{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":1061,"end":1064},"obj":"gene:5663"},{"id":"T1","span":{"begin":994,"end":1025},"obj":"disease:C0276496"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"text":"Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling.\nThe role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients."}

{"project":"DisGeNET5_gene_disease","denotations":[{"id":"18184791-0#29#41#gene5663","span":{"begin":29,"end":41},"obj":"gene5663"},{"id":"18184791-0#18#21#diseaseC0276496","span":{"begin":18,"end":21},"obj":"diseaseC0276496"},{"id":"18184791-6#174#183#gene836","span":{"begin":1168,"end":1177},"obj":"gene836"},{"id":"18184791-6#0#26#diseaseC0276496","span":{"begin":994,"end":1020},"obj":"diseaseC0276496"},{"id":"18184791-9#47#51#gene5290","span":{"begin":1574,"end":1578},"obj":"gene5290"},{"id":"18184791-9#47#51#gene5291","span":{"begin":1574,"end":1578},"obj":"gene5291"},{"id":"18184791-9#47#51#gene5293","span":{"begin":1574,"end":1578},"obj":"gene5293"},{"id":"18184791-9#47#51#gene5294","span":{"begin":1574,"end":1578},"obj":"gene5294"},{"id":"18184791-9#87#90#diseaseC0276496","span":{"begin":1614,"end":1617},"obj":"diseaseC0276496"}],"relations":[{"id":"29#41#gene566318#21#diseaseC0276496","pred":"associated_with","subj":"18184791-0#29#41#gene5663","obj":"18184791-0#18#21#diseaseC0276496"},{"id":"174#183#gene8360#26#diseaseC0276496","pred":"associated_with","subj":"18184791-6#174#183#gene836","obj":"18184791-6#0#26#diseaseC0276496"},{"id":"47#51#gene529087#90#diseaseC0276496","pred":"associated_with","subj":"18184791-9#47#51#gene5290","obj":"18184791-9#87#90#diseaseC0276496"},{"id":"47#51#gene529187#90#diseaseC0276496","pred":"associated_with","subj":"18184791-9#47#51#gene5291","obj":"18184791-9#87#90#diseaseC0276496"},{"id":"47#51#gene529387#90#diseaseC0276496","pred":"associated_with","subj":"18184791-9#47#51#gene5293","obj":"18184791-9#87#90#diseaseC0276496"},{"id":"47#51#gene529487#90#diseaseC0276496","pred":"associated_with","subj":"18184791-9#47#51#gene5294","obj":"18184791-9#87#90#diseaseC0276496"}],"text":"Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling.\nThe role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients."}