Aberrant Axonal Arborization of PDF Neurons Induced by A beta 42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model

作者：Song, Qian; Feng, Ge; Huang, Zehua; Chen, Xiaoman; Chen, Zhaohuan; Ping, Yong^*

来源：Molecular Neurobiology, 2017, 54(8): 6317-6328.

DOI：10.1007/s12035-016-0165-z

• Alzheimer's disease
• Drosophila
• JNK
• Axonal growth
• Sleep

Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila A beta 42 AD model, we show that A beta 42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in A beta 42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in A beta 42 flies. Finally, inhibition of JNK activation in A beta 42 flies restores nighttime sleep loss, decreases A beta 42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by A beta 42 burden, a key initiator of a complex pathogenic cascade in AD.

• 出版日期2017-10
• 单位上海交通大学; 上海市精神卫生中心