长期丰富环境预防淀粉样蛋白诱导突触功能障碍的机制研究

Adverse environmental factors such as stress and head trauma may increase the risk of Alzheimer’s disease which associate with the intracellular neurofibrillary tangles (NFTs) and the extracellular amyloid plaques, while positive environmental factors such as education, cognitive activity and physical exercise help delay its onset. We recently reported (Neuron, 2013) that prolonged exposure of middle-aged wt mice to an enriched environment (EE) protected the hippocampus from the adverse electrophysiological and biochemical effects of soluble Aβ oligomers (oAβ) isolated directly from AD cortex. Pathway analysis showed that enhanced signaling through b2-adrenergic receptors (AR) helped mediate this heightened neural reserve. Our Preliminary Data suggest that EE produces specific patterns of histone acetylation by activating a β2AR/cAMP/PKA/CREB signaling pathway, thus activating CBP and other factors and lessening oAβ synaptotoxicity. Applying histone deacetylase inhibitors orthe β2AR-specific agonist procaterol mimicked EE and protected against oAβ, whereas histone acetyltransferase inhibitors or β2AR KO prevented EE-enhanced LTP. We hypothesize that an EE-activated β2AR signaling cascade regulates certain transcriptional activators and repressors to increase ‘memory gene’ expression, which helps overcome oAβ impairment of synaptic plasticity. This idea is pursued in 3 new Aims:(1) Assess the relative efficacies of mid- and late-life novelty exposure vs. physical exercise in mitigating oAβsynaptic injury and whether β2AR signaling is involved in each; (2) Mechanistically, determine to what extent environmental exposures found in Aim 1 to alleviate oAβ toxicity are mediated by epigenetic effects on DNA and histones.Our results should point to new behavioral and pharmacological approaches to lessen AD dementia.

环境毒素诱导淀粉样蛋白（Aβ）和tau蛋白在中枢神经元内聚集，与阿尔茨海默氏病（AD）密切相关。我们发现，丰富环境（EE）可抵御AD患者脑源性可溶性Aβ寡聚体对成年鼠的突触毒性，β2-肾上腺素受体（β2-AR）在该神经保护机制中起重要作用。我们的初步研究还发现，EE激活β2-AR/ cAMP/PKA/CREB信号通路，通过组蛋白乙酰化，激活CBP等信号因子，减轻Aβ介导的神经毒性，但其分子作用的详细机制不明。因此，我们假设：EE激活β2-AR信号通路，调节相关转录因子表达，阻止Aβ诱导的突触可塑性损害，从而增强大脑记忆功能。为此，本课题拟：1）通过中年鼠与老年鼠的对比研究，分析丰富环境或体育锻炼减轻Aβ诱导的突触损伤机制，以及β2-AR信号通路的相关性；（2）通过揭示环境因素缓解Aβ神经毒性的表观遗传学机制，为AD治疗探索新的方向。

环境毒素诱导淀粉样蛋白（Aβ）和tau蛋白在中枢神经元内聚集，与阿尔茨海默氏病（AD）密切相关。我们发现，丰富环境（EE）可抵御AD患者脑源性可溶性Aβ寡聚体对成年鼠的突触毒性，β2-肾上腺素受体（β2-AR）在该神经保护机制中起重要作用。本课题通过①中年鼠与老年鼠的对比研究，分析丰富环境或体育锻炼减轻Aβ诱导的突触损伤机制，以及β2-AR信号通路的相关性；②通过揭示环境因素缓解Aβ神经毒性的表观遗传学机制。发现EE可以完全阻止可溶性Aβ低聚物对小鼠海马的损害。EE益处的关键分子特征是上调miRNA-132和抑制组蛋白去乙酰化酶（HDAC）信号。可溶性Aβ低聚物降低了培养的原代神经元中miR-132的表达，增加了HDAC3的水平。此外，我们还证实了HDAC3是miR-132的直接靶点的证据。过度表达miR-132或将HDAC3抑制剂注射到标准可溶性Aβ暴露的小鼠体内，模拟了EE的保护作用。可溶性Aβ特异性激活含有NR2B的NMDA受体介导了对LTP的影响。Aβ介导的LTD需要激活钙调神经磷酸酶和GSK-3等信号通路而不是激活p38MAPK信号。明确新的行为学干预和药物干预逆转Aβ对突触的损害，为AD 治疗提供新的方向。