Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Simmaron Research Institute, Technology Innovation Center, 10437 W Innovation Drive, Wauwatosa, WI, USA.
Cell Rep. 2023 Jul 25;42(7):112717. doi: 10.1016/j.celrep.2023.112717. Epub 2023 Jul 11.
This study underlines the importance of β-hydroxy β-methylbutyrate (HMB), a muscle-building supplement in human, in increasing mouse hippocampal plasticity. Detailed proteomic analyses reveal that HMB serves as a ligand of peroxisome proliferator-activated receptor α (PPARα), a nuclear hormone receptor involved in fat metabolism, via interaction with the Y314 residue. Accordingly, HMB is ineffective in increasing plasticity of PPARα hippocampal neurons. While lentiviral establishment of full-length PPARα restores the plasticity-promoting effect of HMB in PPARα hippocampal neurons, lentiviral transduction of Y314D-PPARα remains unable to do that, highlighting the importance of HMB's interaction with the Y314 residue. Additionally, oral HMB improves spatial learning and memory and reduces plaque load in 5X familial Alzheimer's disease (5XFAD) mice, but not in 5XFAD mice (5XFAD lacking PPARα), indicating the involvement of PPARα in HMB-mediated neuroprotection in 5XFAD mice. These results delineate neuroprotective functions of HMB and suggest that this widely used supplement may be repurposed for AD.
这项研究强调了 β-羟基 β-甲基丁酸（HMB）作为一种肌肉增强补充剂在增加小鼠海马体可塑性方面的重要性。详细的蛋白质组学分析表明，HMB 通过与 Y314 残基相互作用，充当过氧化物酶体增殖物激活受体α（PPARα）的配体，PPARα 是一种参与脂肪代谢的核激素受体。因此，HMB 在增加 PPARα 海马神经元的可塑性方面无效。虽然全长 PPARα 的慢病毒建立恢复了 HMB 在 PPARα 海马神经元中促进可塑性的作用，但 Y314D-PPARα 的慢病毒转导仍然无法做到这一点，突出了 HMB 与 Y314 残基相互作用的重要性。此外，口服 HMB 可改善空间学习和记忆，并减少 5X 家族性阿尔茨海默病（5XFAD）小鼠的斑块负荷，但不能减少缺乏 PPARα 的 5XFAD 小鼠（5XFAD 小鼠），表明 PPARα 参与了 HMB 在 5XFAD 小鼠中的神经保护作用。这些结果描绘了 HMB 的神经保护功能，并表明这种广泛使用的补充剂可能被重新用于 AD。
