Effects of 7,8-Dihydroxyflavone on Lipid Isoprenoid and Rho Protein Levels in Brains of Aged C57BL/6 Mice

Effects of 7,8-Dihydroxyflavone on Lipid Isoprenoid and Rho Protein Levels in Brains of Aged C57BL/6 Mice

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 s...

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Bibliographic Details
Published in:Neuromolecular medicine Vol. 23; no. 1; pp. 130 - 139
Main Authors: Ötzkan, Sarah, Muller, Walter E., Gibson Wood, W., Eckert, Gunter P.
Format: Journal Article
Language:English
Published: New York Springer US 01-03-2021
Springer Nature B.V
Subjects:
Aging
Agonists
Biomedical and Life Sciences
Biomedicine
Brain
Brain-derived neurotrophic factor
Cholesterol
Cognitive ability
Cytoskeleton
Dendritic spines
Dimerization
Flavonoids
Guanine
Guanine nucleotide exchange factor
Guanine nucleotide-binding protein
Guanosine triphosphatases
Internal Medicine
Localization
Lymphoma
Metastases
Morphogenesis
Neurology
Neurosciences
Original Paper
Post-translation
Proteins
Rab3A protein
Rac1 protein
Rho protein
Synaptic plasticity
Terpenes
Tiam1 protein
TrkB receptors
Rab3A
Tiam1
Brain aging
BDNF
7,8-dihydroxyflavone
Rac1
Rho proteins
Cholesterol
Isoprenoids
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Summary: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.
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ISSN:1535-1084
1559-1174
DOI:10.1007/s12017-020-08640-0