背景:肥胖是阿尔茨海默病(AD)的一个可改变的危险因素。然而,它与tau病理学的关系(即,tau蛋白在tau蛋白病如AD)中的异常行为尚无定论。
目的:本研究在成年雄性小鼠中研究了高脂饮食(HFD)与tau病理学之间的相互作用。
方法:对过表达人P301STau(有病理的)和野生型(WT)同窝的转基因小鼠进行行为测试,功能磁共振成像(fMRI),扩散张量成像(DTI),和westernblotting分析,以研究成年期长期HFD与常规饮食的影响。
结果:HFD增加WT和P301S小鼠的体重,但对血糖水平的影响最小。对HFD的脑反应是tau基因型特异性的。WT小鼠在功能磁共振成像中表现出识别记忆降低和网络连接增强,而P301S小鼠在DTI中表现出白质道紊乱是唯一的显著发现。胰岛素受体β的减少,胰岛素下游信号,神经元核蛋白,CD68阳性吞噬活性,髓鞘碱性蛋白水平局限于WT小鼠的皮质。与P301S小鼠相比,WT小鼠显示tau蛋白及其磷酸化水平的显着变化,以及海马中可溶性神经丝光水平的增加。
结论:HFD引起的脑功能障碍和病理变化在病理小鼠中减弱,在健康小鼠中更为明显。我们的发现强调了在调整AD和其他tau蛋白病变的治疗策略时,需要考虑肥胖和tau病理之间的这种相互作用。
Obesity is a modifiable risk factor for Alzheimer\'s disease (AD). However, its relation with tau pathology (i.e., aberrant tau protein behavior in tauopathies such as AD) has been inconclusive.
This study investigated the interaction between a high-fat diet (HFD) and tau pathology in adult male mice.
Transgenic mice overexpressing human P301S Tau (those with the pathology) and wild-type (WT) littermates were subjected to behavioral tests, functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and western blotting analysis to investigate the effects of prolonged HFD versus regular diet during adulthood.
HFD increased body weight in both WT and P301S mice but had minimal effect on blood glucose levels. The brain response to HFD was tau genotype-specific. WT mice exhibited decreased recognition memory and enhanced network connectivity in fMRI, while P301S mice exhibited white matter tract disorganization in DTI as the sole significant finding. The reduction of insulin receptor β, insulin downstream signaling, neuronal nuclear protein, CD68-positive phagocytic activity, and myelin basic protein level were confined to the cortex of WT mice. In contrast to P301S mice, WT mice showed significant changes in the tau protein and its phosphorylation levels along with increased soluble neurofilament light levels in the hippocampus.
HFD-induced brain dysfunction and pathological changes were blunted in mice with the pathology and more profound in healthy mice. Our findings highlight the need to consider this interaction between obesity and tau pathology when tailoring treatment strategies for AD and other tauopathies.