Alzheimer's disease-associated tau alters Drosophila circadian activity, sleep and clock neuron electrophysiology
Alzheimer's disease-associated tau alters Drosophila circadian activity, sleep and clock neuron electrophysiology
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DOI：
10.1016/j.nbd.2019.104507
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发表时间：
2019-10-01
影响因子：
6.1
通讯作者：
Hodge, James J. L.
中科院分区：
文献类型：
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作者：
Buhl, Edgar;Higham, James P.;Hodge, James J. L.
阿尔茨海默病(AD)是痴呆症最常见的原因，与世界范围内巨大的个人、社会和经济负担有关。然而，目前的治疗方法很少，没有一种针对这种疾病的根本原因。睡眠和昼夜节律缺陷不仅是AD和其他紧张症的令人痛苦的症状，也是疗养院入院的主要原因，而且被认为加速了AD的病理。尽管如此，人们对这些行为变化的根本原因却知之甚少。Tau的ON4R亚型的表达与AD的病理相关，我们表明，在果蝇的时钟网络中表达它会引起昼夜节律和睡眠表型，这与人类AD患者的行为变化密切匹配。患有自闭症的苍蝇白天和晚上都表现出更大的运动活动，并表现出睡眠不足，特别是在晚上。在持续的黑暗中，表达tau的果蝇的运动行为没有对照组那么有节律性，这表明它们固有的昼夜节律存在缺陷。来自觉醒促进、色素分散因子(PDF)阳性的大型腹侧时钟神经元(1-LNv)的电流钳记录显示，昼夜自发放电增加，这可能是所观察到的过度活跃的昼夜节律表型的基础。有趣的是，只有PDF阳性的起搏器神经元中tau的表达被认为是恒定条件下行为最重要的，但不足以甚至不必要地影响昼夜节律性。这项工作将果蝇建立为一个模型，以研究人类病理版本的tau与控制神经元兴奋性的机制之间的相互作用，从而识别潜在的疾病机制，可能揭示新的治疗靶点。
Alzheimer's disease (AD) is the most common cause of dementia, which is associated with an enormous personal, social and economic burden worldwide. However, there are few current treatments with none of them targeting the underlying causes of the disease. Sleep and circadian rhythm defects are not only distressing symptoms of AD and other tauopathies and are a leading cause of care home admission but are also thought to accelerate AD pathology. Despite this, little is understood about the underlying causes of these behavioural changes. Expression of the ON4R isoform of tau has been associated with AD pathology and we show that expressing it in the Drosophila clock network gives rise to circadian and sleep phenotypes which closely match the behavioural changes seen in human AD patients. Tauopathic flies exhibited greater locomotor activity throughout the day and night and displayed a loss of sleep, particularly at night. Under constant darkness, the locomotor behaviour of tau-expressing flies was less rhythmic than controls indicating a defect in their intrinsic circadian rhythm. Current clamp recordings from wake-promoting, pigment dispersing factor (PDF)-positive large lateral ventral clock neurons (1-LNvs) revealed elevated spontaneous firing throughout the day and night which likely underlies the observed hyperactive circadian phenotype. Interestingly, expression of tau in only the PDF-positive pacemaker neurons, which are thought to be the most important for behaviour under constant conditions, was not sufficient or even necessary to affect circadian rhythmicity. This work establishes Drosophila as a model to investigate interactions between human pathological versions of tau and the machinery that controls neuronal excitability, allowing the identification of underlying mechanisms of disease that may reveal new therapeutic targets.