title: 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's disease.
abstract: Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor/tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Aβ-induced toxicity and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Aβ deposition in transgenic mice that coexpress five familial Alzheimer's disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA [2] Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Schroeder
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Chi-Bun
authors.initials: CB
authors.lastname: Chan
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Mingke
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D047309:Flavones / Q000627:therapeutic use*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000209:etiology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000473:pathology; D013569:Synapses / Q000187:drug effects / Q000473:pathology*
chemical_list: C485383:6,7-dihydroxyflavone; D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D047309:Flavones
references.citation: Prog Neurobiol. 2001 Jan;63(1):71-124
references.pmid: 11040419
references.citation: J Neurosci. 2011 Jan 12;31(2):630-43
references.pmid: 21228172
references.citation: Nature. 2013 Jan 31;493(7434):674-8
references.pmid: 23254930
references.citation: J Neurosci. 2006 Nov 1;26(44):11487-500
references.pmid: 17079678
references.citation: Biol Psychiatry. 2002 Mar 1;51(5):407-16
references.pmid: 11904135
references.citation: Neurobiol Dis. 2009 Feb;33(2):229-35
references.pmid: 19026746
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2711-6
references.pmid: 18263738
references.citation: Behav Genet. 2002 Nov;32(6):435-43
references.pmid: 12467341
references.citation: Nat Rev Neurosci. 2013 Jun;14(6):401-16
references.pmid: 23674053
references.citation: Ann Neurol. 2008 Feb;63(2):204-12
references.pmid: 17894374
references.citation: Nat Neurosci. 1999 Mar;2(3):271-6
references.pmid: 10195221
references.citation: Ann Neurol. 1991 Oct;30(4):572-80
references.pmid: 1789684
references.citation: J Med Chem. 2010 Dec 9;53(23):8274-86
references.pmid: 21073191
references.citation: Nat Med. 2009 Mar;15(3):331-7
references.pmid: 19198615
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2687-92
references.pmid: 20133810
references.citation: Pharmacology. 2013;91(3-4):185-200
references.pmid: 23445871
references.citation: J Neurosci. 2011 Jun 1;31(22):8083-92
references.pmid: 21632930
references.citation: Am J Psychiatry. 2011 Feb;168(2):163-72
references.pmid: 21123312
references.citation: Nat Rev Neurol. 2009 Jun;5(6):311-22
references.pmid: 19498435
references.citation: Curr Alzheimer Res. 2008 Jun;5(3):342-5
references.pmid: 18537547
references.citation: Neurobiol Dis. 2008 Sep;31(3):316-26
references.pmid: 18585459
references.citation: J Neurochem. 2012 Aug;122(4):800-11
references.pmid: 22694088
references.citation: Neuroscience. 1999;88(4):1015-32
references.pmid: 10336117
references.citation: Alzheimers Res Ther. 2013 Apr 29;5(2):21
references.pmid: 23634965
references.citation: Eur J Neurosci. 2009 Dec;30(12):2271-83
references.pmid: 20092570
references.citation: Neuroreport. 1996 Nov 25;7(18):2925-8
references.pmid: 9116211
references.citation: Neuropsychopharmacology. 2012 Jan;37(2):434-44
references.pmid: 21900882
references.citation: J Neuropathol Exp Neurol. 1997 Aug;56(8):933-44
references.pmid: 9258263
references.citation: J Mol Neurosci. 2013 Jan;49(1):96-104
references.pmid: 23054592
references.citation: J Alzheimers Dis. 2011;24(3):547-57
references.pmid: 21297265
references.citation: Mol Cell Neurosci. 2013 Sep;56:115-27
references.pmid: 23639831
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):201-6
references.pmid: 11464953
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2675-80
references.pmid: 20133801
references.citation: Hippocampus. 2012 Mar;22(3):399-408
references.pmid: 21136519
references.citation: J Neurosci. 2006 Oct 4;26(40):10129-40
references.pmid: 17021169
references.citation: J Neurosci. 2012 Nov 28;32(48):17262-72
references.pmid: 23197718
references.citation: J Biol Chem. 2013 Aug 9;288(32):23212-24
references.pmid: 23792961
references.citation: Muscle Nerve. 2012 Feb;45(2):274-6
references.pmid: 22246885
references.citation: Arch Neurol. 1998 Mar;55(3):326-35
references.pmid: 9520006
references.citation: Neurology. 2004 Oct 12;63(7):1155-62
references.pmid: 15477531
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Jun;6(2):100-3
references.pmid: 16036433
references.citation: ACS Chem Neurosci. 2013 May 15;4(5):895-904
references.pmid: 23642472
references.citation: Neuromolecular Med. 2011 Dec;13(4):217-22
references.pmid: 21898045
references.citation: Neuron. 1991 Nov;7(5):695-702
references.pmid: 1742020
references.citation: J Neurosci. 2011 Dec 7;31(49):17800-10
references.pmid: 22159096
references.citation: Neuron. 2003 Jul 31;39(3):409-21
references.pmid: 12895417