Abstract
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.
Highlights
Synaptic impairment may be the main cause of cognitive dysfunction in brain aging instead of neuronal loss (Burke and Barnes 2006; Grillo et al 2013; Morrison and Baxter 2012)
Similar to the previous study on the impact of aging on brain Rho- and Rab-GTPase levels (Afshordel 2010), male C57BL/6 mice aged 3 and 23 months were used as an animal model to study the effects of 7,8-DHF (Fig. 1) on cerebral lipid isoprenoid and Rho protein levels in aged mice
Membrane-bound prenylated Rac1 showed a significant reduction in brain tissue of 23-month-old C57BL/6 mice compared to the 3-month old animals (Fig. 2a)
Summary
Synaptic impairment may be the main cause of cognitive dysfunction in brain aging instead of neuronal loss (Burke and Barnes 2006; Grillo et al 2013; Morrison and Baxter 2012). Age-related synaptic dysfunction is probably due to a reduction in synaptic contact between the axonal buttons and dendritic spines (Hof and Morrison 2004; Mostany et al 2013). Rho proteins including the small GTPase Rac have become key regulators of neuronal morphogenesis that supports synaptic plasticity (Gonzalez-Billault et al 2012). Related to our findings Hottman et al recently published that systemic or forebrain neuron-specific deficiency of GGTase-I reduces dendritic spine density and impairs synaptic plasticity in the brains of young adult mice, concurrently with reduced geranylgeranylation of Rho proteins (Hottman et al 2018)
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