Nuclear receptors as therapeutic targets for Alzheimer's disease.
Nuclear receptors as therapeutic targets for Alzheimer's disease.
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DOI：
10.1517/14728222.2011.594043
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发表时间：
2011-09
影响因子：
5.8
通讯作者：
Landreth GE
中科院分区：
文献类型：
--
作者：
Mandrekar-Colucci S;Landreth GE
阿尔茨海默病（AD）的特点是β淀粉样蛋白在脑实质的积累和广泛沉积。淀粉样蛋白的积累与突触功能紊乱、能量代谢障碍和慢性炎症反应的诱导有关，慢性炎症反应可促进神经元丢失和认知障碍。目前，还没有针对阿尔茨海默病潜在机制的药物。在这里，我们提出一类核受体是阿尔茨海默病的新的和有前途的新的治疗靶点。本文就核受体及其在ad相关病理生理中的作用进行综述。由于核受体能够促进Aβ的降解，影响小胶质细胞的激活和抑制大脑的炎症环境，因此它们是治疗AD的有吸引力的靶点。LXR激动剂已被证明难以进入临床试验，因为长期治疗导致肝脂肪变性。我们认为，PPAR激活仍然是治疗AD的一个有希望的途径，然而，目前可用的激动剂的血脑屏障渗透性差和III期临床试验的负面结果可能会降低追求这一目标的兴趣。
Alzheimer’s disease (AD) is characterized by the accumulation and extensive deposition of amyloid beta in the parenchyma of the brain. This accumulation of amyloid is associated with perturbations in synaptic function, impairments in energy metabolism and induction of a chronic inflammatory response, which acts to promote neuronal loss and cognitive impairment. Currently, there are no drugs that target the underlying mechanisms of Alzheimer’s disease. Here, we propose that a class of nuclear receptors are novel and promising new therapeutic targets for Alzheimer’s disease. This review summarizes the literature on nuclear receptors and their effects on AD-related pathophysiology. Nuclear receptors are attractive targets for the treatment of AD due to their ability to facilitate degradation of Aβ, affect microglial activation and suppress the inflammatory milieu of the brain. LXR agonists have proven difficult to move into clinical trials since long-term treatment results in hepatic steatosis. It is our view that PPARɣ activation remains a promising avenue for the treatment for AD, however, the poor BBB permeability of the currently available agonists and the negative outcome of the phase III clinical trials are likely to diminish interest in pursuing this target.
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