title: Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.
abstract: 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.
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Nathaniel S
authors.initials: NS
authors.lastname: Woodling
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Colas
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Paras
authors.initials: P
authors.lastname: Minhas
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Maharshi
authors.initials: M
authors.lastname: Panchal
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Xibin
authors.initials: X
authors.lastname: Liang
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Siddhita D
authors.initials: SD
authors.lastname: Mhatre
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA 4 Brains On-line LLC, South San Francisco, CA, USA.
authors.forename: Holden
authors.initials: H
authors.lastname: Brown
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Novie
authors.initials: N
authors.lastname: Ko
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Zagol-Ikapitte
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Marieke
authors.initials: M
authors.lastname: van der Hart
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Taline V
authors.initials: TV
authors.lastname: Khroyan
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Bayarsaikhan
authors.initials: B
authors.lastname: Chuluun
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Prachi G
authors.initials: PG
authors.lastname: Priyam
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Rassoulpour
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boutaud
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Manning-Boğ
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: H Craig
authors.initials: HC
authors.lastname: Heller
authors.affiliation: 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA kandreas@stanford.edu.
authors.forename: Katrin I
authors.initials: KI
authors.lastname: Andreasson
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors; D004195:Disease Models, Animal; D015536:Down-Regulation; D004569:Electroencephalography; D015870:Gene Expression / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D007052:Ibuprofen; D008297:Male; D008569:Memory Disorders / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D021641:Recognition, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014366:Tryptophan Oxygenase / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D014366:Tryptophan Oxygenase; D007052:Ibuprofen
keywords: Alzheimer’s disease; cyclooxgenases; hippocampus; ibuprofen; kynurenine pathway