Meilandt William J, Yu Gui-Qiu, Chin Jeannie, Roberson Erik D, Palop Jorge J, Wu Tiffany, Scearce-Levie Kimberly, Mucke Lennart
Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
J Neurosci. 2008 May 7;28(19):5007-17. doi: 10.1523/JNEUROSCI.0590-08.2008.
The enkephalin signaling pathway regulates various neural functions and can be altered by neurodegenerative disorders. In Alzheimer's disease (AD), elevated enkephalin levels may reflect compensatory processes or contribute to cognitive impairments. To differentiate between these possibilities, we studied transgenic mice that express human amyloid precursor protein (hAPP) and amyloid-beta (Abeta) peptides in neurons and exhibit key aspects of AD. Met-enkephalin levels in neuronal projections from the entorhinal cortex and dentate gyrus (brain regions important for memory that are affected in early stages of AD) were increased in hAPP mice, as were preproenkephalin mRNA levels. Genetic manipulations that exacerbate or prevent excitotoxicity also exacerbated or prevented the enkephalin alterations. In human AD brains, enkephalin levels in the dentate gyrus were also increased. In hAPP mice, enkephalin elevations correlated with the extent of Abeta-dependent neuronal and behavioral alterations, and memory deficits were reduced by irreversible blockade of mu-opioid receptors with the antagonist beta-funaltrexamine. We conclude that enkephalin elevations may contribute to cognitive impairments in hAPP mice and possibly in humans with AD. The therapeutic potential of reducing enkephalin production or signaling merits further exploration.
脑啡肽信号通路调节多种神经功能，且会因神经退行性疾病而改变。在阿尔茨海默病（AD）中，脑啡肽水平升高可能反映了代偿过程，或导致认知障碍。为区分这些可能性，我们研究了在神经元中表达人淀粉样前体蛋白（hAPP）和β-淀粉样蛋白（Aβ）肽并表现出AD关键特征的转基因小鼠。在内嗅皮质和齿状回（对记忆很重要且在AD早期阶段会受影响的脑区）的神经投射中，hAPP小鼠的甲硫氨酸脑啡肽水平升高，前脑啡肽原mRNA水平也升高。加剧或预防兴奋性毒性的基因操作也加剧或预防了脑啡肽的改变。在人类AD大脑中，齿状回中的脑啡肽水平也升高。在hAPP小鼠中，脑啡肽升高与Aβ依赖性神经元和行为改变的程度相关，且用拮抗剂β-芬太尼环已胺不可逆地阻断μ-阿片受体可减少记忆缺陷。我们得出结论，脑啡肽升高可能导致hAPP小鼠以及可能患有AD人类的认知障碍。降低脑啡肽产生或信号传导的治疗潜力值得进一步探索。
