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Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.

Authors: Woodling, Nathaniel S  Colas, Damien  Wang, Qian  Minhas, Paras  Panchal, Maharshi  Liang, Xibin  Mhatre, Siddhita D  Brown, Holden  Ko, Novie  Zagol-Ikapitte, Irene  van der Hart, Marieke  Khroyan, Taline V  Chuluun, Bayarsaikhan  Priyam, Prachi G  Milne, Ginger L  Rassoulpour, Arash  Boutaud, Olivier  Manning-Bog, Amy B  Heller, H Craig  Andreasson, Katrin I 
Citation: Woodling NS, etal., Brain. 2016 Jul;139(Pt 7):2063-81. doi: 10.1093/brain/aww117. Epub 2016 May 13.
Pubmed: (View Article at PubMed) PMID:27190010
DOI: Full-text: DOI:10.1093/brain/aww117

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-PS1¿E9 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-ß 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-PS1¿E9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-ß oligomers.


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CRRD Object Information
CRRD ID: 13601984
Created: 2018-05-25
Species: All species
Last Modified: 2018-05-25
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.