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-Boğ Amy B, Heller H Craig, Andreasson Katrin I
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.
1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Brain. 2016 Jul;139(Pt 7):2063-81. doi: 10.1093/brain/aww117. Epub 2016 May 13.
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.
确定阿尔茨海默病的预防靶点是现代医学的一项核心挑战。非甾体抗炎药可抑制环氧化酶COX - 1和COX - 2，降低正常老龄化人群患阿尔茨海默病的风险。这种预防作用与认知能力下降出现前长达数年至数十年的临床前期延长相吻合。在大脑中，COX - 2在神经元中因兴奋性突触活动而被诱导，在胶质细胞中因炎症而被诱导。为了确定抗炎药物预防认知能力下降的潜在机制，我们首先在APPSwe - PS1ΔE9小鼠中发现了一种早期物体记忆缺陷，该缺陷早于该模型中先前确定的空间记忆缺陷。我们用布洛芬模拟对这种记忆缺陷的预防，发现布洛芬可预防记忆损伤，而不会在淀粉样β蛋白积累或胶质细胞炎症方面产生任何可测量的变化。相反，布洛芬调节了参与神经元可塑性的海马体基因表达，并提高了去甲肾上腺素和多巴胺的水平。被布洛芬下调程度最高的基因是神经元色氨酸2,3 - 双加氧酶（Tdo2），它编码一种将色氨酸代谢为犬尿氨酸的酶。TDO2的表达因神经元COX - 2活性而增加，海马体TDO2的过表达会导致行为缺陷。此外，药理学上对TDO2的抑制可预防APPSwe - PS1ΔE9小鼠的行为缺陷。综上所述，这些数据表明环氧化酶抑制对多种神经元通路具有广泛影响，可抵消早期积累的淀粉样β寡聚体的神经毒性作用。
