TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease

Lei Gao, Mi Tian, Hong Yun Zhao, Qian Qian Xu, Yu Ming Huang, Qun Cao Si, Qing Tian, Qing Ming Wu, Xia Min Hu, Li Bo Sun, Shawn M. McClintock, Yan Zeng

Research output: Contribution to journalArticle

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Abstract

We recently demonstrated that activation of tyrosine receptor kinase B (TrkB) by 7, 8-dihydroxyflavone (7, 8-DHF), the selective TrkB agonist, increased surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPARs) AMPA receptor subunit GluR1 (GluA1) subunit expression at the synapses of Fragile X Syndrome mutant mice. This present study investigated the effects of 7, 8-DHF on both memory function and synapse structure in relation to the synapse protein level of AMPARs in the Tg2576 Alzheimer's disease (AD) mouse model. The study found that chronic oral administration of 7, 8-DHF significantly improved spatial memory and minimized dendrite loss in the hippocampus of Tg2576 mice. A key feature of 7, 8-DHF action was the increased expression of both GluA1 and GluA2 at synapses. Interestingly, 7, 8-DHF had no effect on the attenuation of amyloid precursor protein or Aβ exhibiting in the Tg2576 AD brains, yet it activated the phosphorylation of TrkB receptors and its downstream signals including CaMKII, Akt, Erk1/2, and cAMP-response element-binding protein. Importantly, cyclotraxin B (a TrkB inhibitor), U0126 (a Ras-ERK pathway inhibitor), Wortmannin (an Akt phosphorylation inhibitor), and KN-93 (a CaMKII inhibitor) counteracted the enhanced expression and phosphorylation of AMPAR subunits induced by 7, 8-DHF. Collectively, our results demonstrated that 7, 8-DHF acted on TrkB and resolved learning and memory impairments in the absence of reduced amyloid in amyloid precursor protein transgenic mice partially through improved synaptic structure and enhanced synaptic AMPARs. The findings suggest that the application of 7, 8-DHF may be a promising new approach to improve cognitive abilities in AD.

Original languageEnglish (US)
Pages (from-to)620-636
Number of pages17
JournalJournal of Neurochemistry
Volume136
Issue number3
DOIs
StatePublished - Feb 1 2016

Fingerprint

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Memory Disorders
Receptor Protein-Tyrosine Kinases
Synapses
Alzheimer Disease
Chemical activation
Data storage equipment
AMPA Receptors
Phosphorylation
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Amyloid beta-Protein Precursor
Isoxazoles
Serum Amyloid A Protein
Fragile X Syndrome
Cyclic AMP Response Element-Binding Protein
Neurotransmitter Receptor
Aptitude
Spatial Memory
6,7-dihydroxyflavone
MAP Kinase Signaling System

Keywords

  • 7, 8-dihydroxyflavone
  • AMPA receptors
  • cognitive impairment
  • synapse structure
  • Tg2576 mouse
  • TrkB signaling

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease. / Gao, Lei; Tian, Mi; Zhao, Hong Yun; Xu, Qian Qian; Huang, Yu Ming; Si, Qun Cao; Tian, Qing; Wu, Qing Ming; Hu, Xia Min; Sun, Li Bo; McClintock, Shawn M.; Zeng, Yan.

In: Journal of Neurochemistry, Vol. 136, No. 3, 01.02.2016, p. 620-636.

Research output: Contribution to journalArticle

Gao, Lei ; Tian, Mi ; Zhao, Hong Yun ; Xu, Qian Qian ; Huang, Yu Ming ; Si, Qun Cao ; Tian, Qing ; Wu, Qing Ming ; Hu, Xia Min ; Sun, Li Bo ; McClintock, Shawn M. ; Zeng, Yan. / TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease. In: Journal of Neurochemistry. 2016 ; Vol. 136, No. 3. pp. 620-636.
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AU - Xu, Qian Qian

AU - Huang, Yu Ming

AU - Si, Qun Cao

AU - Tian, Qing

AU - Wu, Qing Ming

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AU - Sun, Li Bo

AU - McClintock, Shawn M.

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