Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways
| Autor: | Ettcheto Arriola, Miren, Sánchez-López, E. (Elena), Pons, Laura, Busquets Figueras, Oriol, Olloquequi González, Jordi, Beas Zárate, Carlos, Pallàs i Llibería, Mercè, 1964, García López, María Luisa, Auladell i Costa, M. Carme, Folch, Jaume, Camins Espuny, Antoni |
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| Přispěvatelé: | Universitat de Barcelona |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
GFAP
Glial Fibrillary Acidic Protein ADAM10 Disintegrin and metalloproteinase domain-containing protein 10 MAPK Mitogen-activated protein kinase BACE1 β-secretase 1 CDK5 Cyclin-dependent kinase 5 Ibuprofen IBU Ibuprofen Hippocampus Mitocondris PFA Paraformaldehide PPARγ Peroxisome proliferator-activated receptor-γ Amyloid beta-Protein Precursor Mice Cognition DXI Dexibuprofen APPSwe/PS1dE9 Aspartic Acid Endopeptidases Proto-Oncogene Proteins c-abl PKA Protein kinase A lcsh:QH301-705.5 lcsh:R5-920 DI Discrimination index Brain Drugs COX-1 Cyclooxygenase-1 NORT Novel object recognition test IDE Insulin-degrading enzyme Memory impairment Alzheimer's disease Mitochondria TNF-α Tumor necrosis factor Neuroprotective Agents pTAU Phospho-TAU SYP Synaptophysin Female AD Alzheimer's disease lcsh:Medicine (General) Hippocampus (Brain) Medicaments Research Paper Signal Transduction APP/PS1 APPswe/PS1dE9 NSAIDs Non-steroidal anti-inflammatory drugs Hipocamp (Cervell) NFĸβ Nuclear factor kappa beta c-ABL Abelson non-receptor tyrosine kinase tau Proteins COX-2 Cyclooxygenase-2 Alzheimer Disease Cyclins GSK3β Glycogen synthase kinase 3β Aβ Amyloid beta Presenilin-1 Animals Insulin receptors Tumor Necrosis Factor-alpha Cyclin-Dependent Kinase 5 Receptors d'insulina Phosphoproteins iNOS Inducible nitric oxide synthase Mice Inbred C57BL Dexibuprofen MWM Morris water maze Malaltia d'Alzheimer lcsh:Biology (General) nNOS Neuronal Nitric Oxide Synthase Amyloid Precursor Protein Secretases TAU Carrier Proteins APP Amyloid precursor protein NFTs Neurofibrillary tangles WT Wild type Insulin receptor |
| Zdroj: | Redox Biology, Vol 13, Iss C, Pp 345-352 (2017) Redox Biology Recercat. Dipósit de la Recerca de Catalunya instname Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks. Graphical abstract fx1 Highlights • DXI treatment improves cognitive impairment in APPswe/PS1dE9 mice through multiple targets. • Aβ reduction occurs with DXI inhibiting APP, BACE1 and increasing IDE1 hippocampal protein levels. • DXI contributes to TAU hyperphosphorylation decreasing but does not alter total TAU expression. • CDK5 pathway is altered by DXI inhibiting CDK5 phosphorylation via TNFα/c-ABLl/CABLES. • DXI decreases pAKT/pGSK3β protein levels which are involved in insulin signaling pathway. |
| Databáze: | OpenAIRE |
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