D'Orio Barbara, Fracassi Anna, Ceru Maria Paola, Moreno Sandra
Department of Science-LIME, University Roma Tre, Rome, Italy.
Curr Alzheimer Res. 2018 Feb 22;15(4):345-354. doi: 10.2174/1567205014666170505094549.
The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called "amyloid cascade hypothesis" has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD.
This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.
阿尔茨海默病（AD）的分子机制尚未完全阐明。长期以来，所谓的“淀粉样蛋白级联假说”一直是该疾病病因的主流范式，如今正结合其他致病途径（如氧化应激、神经炎症和能量代谢异常）重新审视。过氧化物酶体增殖物激活受体（PPARs）在中枢神经系统（CNS）中表达，并调节许多生理过程，如能量代谢、神经传递、氧化还原稳态、自噬和细胞周期。在三种亚型（α、β/δ、γ）中，PPARγ的作用研究最为广泛，而关于α和β/δ的信息仍然匮乏。然而，最近的体外和体内证据表明PPARα是AD中有前景的治疗靶点。
本综述提供了关于该主题的最新信息，重点关注天然或合成激动剂在调节AD发病和进展过程中致病机制方面的作用。配体激活的PPARα可抑制淀粉样蛋白生成途径、Tau蛋白过度磷酸化和神经炎症。同时，该受体可引发针对氧化应激的酶促抗氧化反应，改善葡萄糖和脂质代谢异常，并刺激自噬。
