Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice
| Autor: | Ginger L. Milne, Taline V. Khroyan, Marieke van der Hart, Katrin I. Andreasson, H. Craig Heller, Prachi Priyam, Amy B. Manning-Boğ, Damien Colas, Bayarsaikhan Chuluun, Irene Zagol-Ikapitte, Qian Wang, Nathaniel S. Woodling, Paras S. Minhas, Xibin Liang, Maharshi Panchal, Siddhita D. Mhatre, Novie Ko, Arash Rassoulpour, Olivier Boutaud, Holden D. Brown |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Modern medicine Kynurenine pathway Hippocampus Down-Regulation Gene Expression Ibuprofen Pharmacology 03 medical and health sciences Mice 0302 clinical medicine Dopamine Alzheimer Disease medicine Animals Cyclooxygenase Inhibitors Cognitive decline Neurons Memory Disorders Neuronal Plasticity biology Behavior Animal organic chemicals Electroencephalography Recognition Psychology Original Articles medicine.disease Tryptophan Oxygenase Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology Synaptic plasticity biology.protein Neurology (clinical) Cyclooxygenase Alzheimer's disease Psychology Neuroscience 030217 neurology & neurosurgery medicine.drug Signal Transduction |
| Zdroj: | Brain : a journal of neurology. 139(Pt 7) |
| ISSN: | 1460-2156 |
| Popis: | Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers. |
| Databáze: | OpenAIRE |
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