Premium
P3‐121: Small Molecule 7, 8‐Dihydroxyflavone Activating TRKB Receptor for Treating Fragile X Syndrome and Alzheimer’s Disease
Author(s) -
Zeng Yan
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1779
Subject(s) - tropomyosin receptor kinase b , ampa receptor , fmr1 , fragile x syndrome , neuroscience , dendritic spine , receptor , psychology , biology , chemistry , neurotrophic factors , nmda receptor , medicine , hippocampal formation , psychiatry , biochemistry , gene , fragile x
Background: 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist, which mimic BDNF’s neurotrophic signaling and overcome the pharmacokinetic and side effect barriers. Our recent work suggest that 7, 8-DHF is able to bind and activate TrkB, and rescue BDNF deficits in Alzheimer’s disease (AD), the most common form of dementia in elderly adults, and Fragile X syndrome (FXS), the most common form of inherited intellectual disability. Methods: We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7,8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile Xmental retardation 1 (Fmr1) gene knock-out mice and Tg2576 ADmice.Results:Wefound a large positive effect from 7, 8-DHF on learning and memory in fragile Xmental retardation 1 (Fmr1) gene knock-out mice and the Tg2576 AD mouse model. A long term treatment with 7, 8-DHF improves spatial and fear learning and memory that depend on hippocampus and amygdala. 7, 8-DHF also ameliorates morphological spine abnormalities. Further mechanism analysis reveals that 7, 8-DHF increases the phosphorylation of TrkB and enhances synapse expression of GluA1 of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses leads to the phosphorylation of (i) specific serine sites including Ser818 and Ser813 of GluA1, and Ser880 of GluA2, and (ii) calcium/calmodulin-dependent protein kinase II and protein kinase C, two kinases that target these sites. 7, 8-DHF activated the phosphorylation of TrkB receptors and its downstream signals including CaMKII, Akt, Erk1/2, and cAMP-response elementbinding protein.Conclusions: Collectively, our results demonstrated that 7, 8-DHF acted on TrkB and resolved learning and memory impairments in Fmr1 gene knock-out mice and amyloid precursor protein transgenic mice partially through improving synaptic structure and enhanced synaptic AMPARs. Thus our works provide a potential therapeutic tool for FXS and AD treatment.