D'Andrea Giorgio, Ceccarelli Manuela, Bernini Roberta, Clemente Mariangela, Santi Luca, Caruso Carla, Micheli Laura, Tirone Felice
Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Monterotondo, Rome, Italy.
Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy.
FASEB J. 2020 Mar;34(3):4512-4526. doi: 10.1096/fj.201902643R. Epub 2020 Feb 6.
The dentate gyrus of the hippocampus is one of two brain areas generating throughout life new neurons, which contribute to the formation of episodic/associative memories. During aging, the production of new neurons decreases and a cognitive decline occurs. Dietary factors influence neuronal function and synaptic plasticity; among them the phenolic compound hydroxytyrosol (HTyr), present in olive oil, displays neuroprotective effects. As age impacts primarily on the hippocampus-dependent cognitive processes, we wondered whether HTyr could stimulate hippocampal neurogenesis in vivo in adult and aged wild-type mice as well as in the B-cell translocation 1 gene (Btg1) knockout mouse model of accelerated neural aging. We found that treatment with HTyr activates neurogenesis in the dentate gyrus of adult, aged, and Btg1-null mice, by increasing survival of new neurons and decreasing apoptosis. Notably, however, in the aged and Btg1-null dentate gyrus, HTyr treatment also stimulates the proliferation of stem and progenitor cells, whereas in the adult dentate gyrus HTyr lacks any proliferative effect. Moreover, the new neurons generated in aged mice after HTyr treatment are recruited to existing circuits, as shown by the increase of BrdU /c-fos neurons. Finally, HTyr treatment also reduces the markers of aging lipofuscin and Iba1. Overall, our findings indicate that HTyr treatment counteracts neurogenesis decline during aging.
海马体的齿状回是一生中产生新神经元的两个脑区之一，这些新神经元有助于情景/联想记忆的形成。在衰老过程中，新神经元的产生减少，认知能力下降。饮食因素会影响神经元功能和突触可塑性；其中，橄榄油中含有的酚类化合物羟基酪醇（HTyr）具有神经保护作用。由于年龄主要影响依赖海马体的认知过程，我们想知道HTyr是否能在成年和老年野生型小鼠以及加速神经衰老的B细胞易位1基因（Btg1）敲除小鼠模型中体内刺激海马体神经发生。我们发现，HTyr处理通过增加新神经元的存活率和减少细胞凋亡，激活成年、老年和Btg1基因缺失小鼠齿状回中的神经发生。然而，值得注意的是，在老年和Btg1基因缺失的齿状回中，HTyr处理还能刺激干细胞和祖细胞的增殖，而在成年齿状回中，HTyr没有任何增殖作用。此外，HTyr处理后老年小鼠中产生的新神经元被招募到现有神经回路中，这一点通过BrdU/c-fos神经元的增加得以证明。最后，HTyr处理还能减少衰老标志物脂褐素和Iba1。总体而言，我们的研究结果表明，HTyr处理可抵消衰老过程中神经发生的下降。
