Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer's disease through inhibition of inflammation.
Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer's disease through inhibition of inflammation.
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通过抑制炎症，在阿尔茨海默氏病的转基因小鼠模型中，核受体PPARδ的激活是神经保护作用。
DOI：
10.1186/s12974-014-0229-9
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发表时间：
2015-01-16
影响因子：
9.3
通讯作者：
Landreth GE
中科院分区：
文献类型：
--
作者：
Malm T;Mariani M;Donovan LJ;Neilson L;Landreth GE
阿尔茨海默病 (AD) 是一种多因素疾病，与可溶性 β-淀粉样蛋白 (Aβ) 的积累及其随后沉积成斑块相关。神经元死亡的主要原因之一是斑块周围小胶质细胞的慢性且不受控制的炎症激活及其神经毒性分子的分泌。已提出小胶质细胞活化向吞噬表型的转变可为 AD 模型带来益处。过氧化物酶体增殖物激活受体 δ (PPARδ) 是一种具有有效抗炎激活特性的转录因子，PPARδ 激动作用可导致 5XFAD 小鼠脑内 Aβ 水平降低。本研究的目的是阐明小胶质细胞激活在 PPARδ 介导的 Aβ 负荷减少中的作用以及随后在 5XFAD 小鼠 AD 模型中神经元存活的结果。 5XFAD 小鼠口服 PPARδ 激动剂 GW0742 2 周。通过免疫组织化学和定量 PCR 评估大脑 Aβ 负载、神经胶质活化和神经元存活。此外，还在体外分析了 GW0742 预防直接神经元死亡以及炎症诱导的神经元死亡的能力。我们的结果首次表明，5XFAD 小鼠的短期治疗可有效降低实质 Aβ 负荷，而不影响神经元内 Aβ 水平。这伴随着整体小胶质细胞活化的减少和促炎介质的减少。相反，Aβ 沉积物周围的小胶质细胞免疫反应性增加。重要的是，GW0742 治疗引起的促炎环境减少导致 5XFAD 小鼠下托体内神经元损失减少。此外，虽然 GW0742 未能保护原代神经元免受谷氨酸诱导的细胞死亡，但它在体外小胶质细胞-神经元共培养物中阻止了炎症诱导的神经元死亡。这项研究表明，GW0742 治疗对 5XFAD 小鼠具有显着的抗炎作用，并表明 PPARδ 激动剂可能在治疗 AD 方面具有治疗效用。
Alzheimer’s disease (AD) is a multifactorial disorder associated with the accumulation of soluble forms of beta-amyloid (Aβ) and its subsequent deposition into plaques. One of the major contributors to neuronal death is chronic and uncontrolled inflammatory activation of microglial cells around the plaques and their secretion of neurotoxic molecules. A shift in microglial activation towards a phagocytic phenotype has been proposed to confer benefit in models of AD. Peroxisome proliferator activator receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory activation properties and PPARδ agonism leads to reduction in brain Aβ levels in 5XFAD mice. This study was carried out to elucidate the involvement of microglial activation in the PPARδ-mediated reduction of Aβ burden and subsequent outcome to neuronal survival in a 5XFAD mouse model of AD. 5XFAD mice were orally treated with the PPARδ agonist GW0742 for 2 weeks. The brain Aβ load, glial activation, and neuronal survival were assessed by immunohistochemistry and quantitative PCR. In addition, the ability of GW0742 to prevent direct neuronal death as well as inflammation-induced neuron death was analyzed in vitro. Our results show for the first time that a short treatment period of 5XFAD mice was effective in reducing the parenchymal Aβ load without affecting the levels of intraneuronal Aβ. This was concomitant with a decrease in overall microglial activation and reduction in proinflammatory mediators. Instead, microglial immunoreactivity around Aβ deposits was increased. Importantly, the reduction in the proinflammatory milieu elicited by GW0742 treatment resulted in attenuation of neuronal loss in vivo in the subiculum of 5XFAD mice. In addition, whereas GW0742 failed to protect primary neurons against glutamate-induced cell death, it prevented inflammation-induced neuronal death in microglia-neuron co-cultures in vitro. This study demonstrates that GW0742 treatment has a prominent anti-inflammatory effect in 5XFAD mice and suggests that PPARδ agonists may have therapeutic utility in treating AD.
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DOI：
10.1038/mt.2009.44
发表时间：
2009-05
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Kersten, S;Desvergne, B;Wahli, W
通讯作者：
Wahli, W
影响因子：
4.8
作者：
Lee, C. Y. Daniel;Tse, Wayne;Landreth, Gary E.
通讯作者：
Landreth, Gary E.
DOI：
10.1124/jpet.106.115758
发表时间：
2007-03-01
影响因子：
3.5
作者：
Iwashita, Akinori;Muramatsu, Yuko;Matsuoka, Nobuya
通讯作者：
Matsuoka, Nobuya
影响因子：
2.5
作者：
Cannon, Jason R.;Greenamyre, J. Timothy
通讯作者：
Greenamyre, J. Timothy