突触损伤可能是大脑衰老中认知功能障碍的主要原因,这可能是由于轴突纽扣和树突棘之间的突触接触减少所致。包括小GTP酶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因子。小的Rhos和Ras-GTPases被类异戊二烯香叶基香叶基香叶基焦磷酸(GGD)和法尼基焦磷酸(FPP)翻译后修饰,分别。对于所有GTPases,锚定在质膜中对于鸟嘌呤核苷酸交换因子(GEF)的激活至关重要。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,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)充当高度亲和选择性TrkB受体激动剂,并引起TrkB受体的二聚化和自磷酸化,从而激活下游信号传导途径。在目前的研究中,我们研究了7,8-DHF对3和23月龄雄性C57BL/6小鼠脑脂质类异戊二烯和Rho蛋白水平的影响。通过口服管饲法每天用100mg/kgb.w.7,8-DHF治疗老年小鼠21天。FPP,G3GPP,测定脑组织中的胆固醇水平。在同一组织中,测定了Tiam1和TrkB中的蛋白质含量。在全脑匀浆和膜制剂中研究了小Rho-GTP酶Rac1和小Rab-GTP酶Rab3A的细胞定位。我们报告了新发现,即7,8-DHF恢复了从治疗的老年小鼠大脑中分离出的膜制剂中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的Tiam1水平降低。FPP,G3GPP,老年小鼠大脑中的胆固醇水平显着升高,但7,8-DHF治疗没有改变。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,尽管潜在的机制需要详细阐明。
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.