Synaptic impairment may be the main cause of cognitive dysfunction in brain aging that is probably due to a reduction in synaptic contact between the axonal buttons and dendritic spines. Rho proteins including the small GTPase Rac1 have become key regulators of neuronal morphogenesis that supports synaptic plasticity. Small Rho- and Ras-GTPases are post-translationally modified by the isoprenoids geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), respectively. For all GTPases, anchoring in the plasma membrane is essential for their activation by guanine nucleotide exchange factors (GEFs). Rac1-specific GEFs include the protein T lymphoma invasion and metastasis 1 (Tiam1). Tiam1 interacts with the TrkB receptor to mediate the brain-derived neurotrophic factor (BDNF)-induced activation of Rac1, resulting in cytoskeletal rearrangement and changes in cellular morphology. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) acts as a highly affine-selective TrkB receptor agonist and causes the dimerization and autophosphorylation of the TrkB receptor and thus the activation of downstream signaling pathways. In the current study, we investigated the effects of 7,8-DHF on cerebral lipid isoprenoid and Rho protein levels in male C57BL/6 mice aged 3 and 23 months. Aged mice were daily treated with 100 mg/kg b.w. 7,8-DHF by oral gavage for 21 days. FPP, GGPP, and cholesterol levels were determined in brain tissue. In the same tissue, the protein content of Tiam1 and TrkB in was measured. The cellular localization of the small Rho-GTPase Rac1 and small Rab-GTPase Rab3A was studied in total brain homogenates and membrane preparations. We report the novel finding that 7,8-DHF restored levels of the Rho proteins Rac1 and Rab3A in membrane preparations isolated from brains of treated aged mice. The selective TrkB agonist 7,8-DHF did not affect BDNF and TrkB levels, but restored Tiam1 levels that were found to be reduced in brains of aged mice. FPP, GGPP, and cholesterol levels were significantly elevated in brains of aged mice but not changed by 7,8-DHF treatment. Hence, 7,8-DHF may be useful as pharmacological tool to treat age-related cognitive dysfunction although the underlying mechanisms need to be elucidated in detail.

突触损伤可能是大脑老化认知功能障碍的主要原因，这可能是由于轴突按钮和树突棘之间的突触接触减少。包括小 GTPase Rac1 在内的 Rho 蛋白已成为支持突触可塑性的神经元形态发生的关键调节剂。小 Rho- 和 Ras-GTP 酶分别由类异戊二烯香叶基香叶基焦磷酸 (GGPP) 和法呢基焦磷酸 (FPP) 进行翻译后修饰。对于所有 GTP 酶，锚定在质膜中对于它们被鸟嘌呤核苷酸交换因子 (GEF) 激活至关重要。Rac1 特异性 GEF 包括蛋白 T 淋巴瘤侵袭和转移 1 (Tiam1)。Tiam1 与 TrkB 受体相互作用以介导脑源性神经营养因子 (BDNF) 诱导的 Rac1 激活，导致细胞骨架重排和细胞形态变化。类黄酮 7,8-二羟基黄酮 (7,8-DHF) 作为高度亲和选择性的 TrkB 受体激动剂，导致 TrkB 受体的二聚化和自磷酸化，从而激活下游信号通路。在当前的研究中，我们研究了 7,8-DHF 对 3 个月和 23 个月大的雄性 C57BL/6 小鼠脑脂质类异戊二烯和 Rho 蛋白水平的影响。老年小鼠每天通过口服强饲法用 100 毫克/千克体重的 7,8-DHF 治疗 21 天。在脑组织中测定 FPP、GGPP 和胆固醇水平。在同一组织中，测量了 Tiam1 和 TrkB 的蛋白质含量。在全脑匀浆和膜制剂中研究了小 Rho-GTPase Rac1 和小 Rab-GTPase Rab3A 的细胞定位。我们报告了一项新发现，即 7,8-DHF 恢复了从接受治疗的老年小鼠大脑中分离的膜制剂中 Rho 蛋白 Rac1 和 Rab3A 的水平。选择性 TrkB 激动剂 7,8-DHF 不影响 BDNF 和 TrkB 水平，但恢复了在老年小鼠大脑中发现降低的 Tiam1 水平。FPP、GGPP 和胆固醇水平在老年小鼠大脑中显着升高，但在 7,8-DHF 治疗中没有改变。因此，7,8-DHF 可用作治疗与年龄相关的认知功能障碍的药理学工具，尽管需要详细阐明其潜在机制。但恢复了 Tiam1 水平，发现老年小鼠大脑中的 Tiam1 水平降低。FPP、GGPP 和胆固醇水平在老年小鼠大脑中显着升高，但在 7,8-DHF 治疗中没有改变。因此，7,8-DHF 可用作治疗与年龄相关的认知功能障碍的药理学工具，尽管需要详细阐明其潜在机制。但恢复了 Tiam1 水平，发现老年小鼠大脑中的 Tiam1 水平降低。FPP、GGPP 和胆固醇水平在老年小鼠大脑中显着升高，但在 7,8-DHF 治疗中没有改变。因此，7,8-DHF 可用作治疗与年龄相关的认知功能障碍的药理学工具，尽管需要详细阐明其潜在机制。