Takei Yoshinori, Amagase Yoko, Goto Ai, Kambayashi Ryuichi, Izumi-Nakaseko Hiroko, Hirasawa Akira, Sugiyama Atsushi
Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-Ku, Tokyo, 143-8540, Japan.
YOKOYAMA Kazuya Cancer Research Institute, 2F Ueno Yokoyama Bidg, 1-4-8 Ueno, Taito-Ku, Tokyo, 110-0005, Japan.
Geroscience. 2025 Feb 13. doi: 10.1007/s11357-025-01546-4.
Aging alters signaling that involves brain-derived neurotrophic factor (BDNF) in the hippocampus. An adequate level of BDNF is essential for maintaining cognitive function in older adults. Previously, we showed that repeated intraperitoneal administration of the chemokine ligand CX3CL1 modulates peritoneal immune cells and the vagal nerve to increase hippocampal BDNF, consequently improving cognitive decline in aged mice. Here, we examined the contribution of endogenous CX3CL1 in the peritoneal cavity to the age-associated regulation of hippocampal BDNF levels. Hippocampal BDNF protein levels were comparable between 5-month-old and 10-month-old mice but were reduced in 18-month-old. CX3CL1 expression in the visceral adipose tissue, which is prominent in the peritoneal cavity, was also lower in 18-month-old mice than in 10-month-old mice. Visceral adipose tissue-specific knockdown of CX3CL1 reduced hippocampal BDNF levels in 10-month-old mice. Reciprocally, a single intraperitoneal injection of CX3CL1 recovered hippocampal BDNF levels in 18-month-old mice. Moreover, the naturally occurring glucocorticoids, corticosterone and hydrocortisone, increased CX3CL1 expression in a concentration-dependent manner. In the visceral adipose tissue, both protein level and enzymatic activity of the glucocorticoid activating enzyme 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1) were lower in 18-month-old mice than in 10-month-old. Tissue-specific knockdown of 11β-HSD1 in visceral adipose tissue decreased both adipose CX3CL1 expression and hippocampal BDNF levels in 10-month-old mice. Our results demonstrate that adipose CX3CL1 is involved in maintaining hippocampal BDNF levels. This inter-tissue crosstalk is impaired in aged mice due to low 11β-HSD1 expression in visceral adipose tissue, which contributes to the age-associated decline in hippocampal BDNF.
衰老会改变海马体中涉及脑源性神经营养因子（BDNF）的信号传导。足够水平的BDNF对于维持老年人的认知功能至关重要。此前，我们发现反复腹腔注射趋化因子配体CX3CL1可调节腹腔免疫细胞和迷走神经，以增加海马体中的BDNF，从而改善老年小鼠的认知衰退。在此，我们研究了腹腔内内源性CX3CL1对海马体BDNF水平与年龄相关调节的作用。5个月大的小鼠和10个月大的小鼠海马体BDNF蛋白水平相当，但18个月大的小鼠中该水平降低。在腹腔中占主导地位的内脏脂肪组织中，18个月大的小鼠CX3CL1表达也低于10个月大的小鼠。在内脏脂肪组织中特异性敲低CX3CL1可降低10个月大小鼠的海马体BDNF水平。相反，单次腹腔注射CX3CL1可恢复18个月大小鼠的海马体BDNF水平。此外，天然存在的糖皮质激素皮质酮和氢化可的松以浓度依赖的方式增加CX3CL1表达。在内脏脂肪组织中，糖皮质激素激活酶11β-羟基类固醇脱氢酶1型（11β-HSD1）的蛋白水平和酶活性在18个月大的小鼠中均低于10个月大的小鼠。在内脏脂肪组织中特异性敲低11β-HSD1可降低10个月大小鼠的脂肪CX3CL1表达和海马体BDNF水平。我们的结果表明，脂肪CX3CL1参与维持海马体BDNF水平。由于内脏脂肪组织中11β-HSD1表达较低，这种组织间的串扰在老年小鼠中受损，这导致了与年龄相关的海马体BDNF下降。
