title: Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease.
abstract: In the mitochondria-mediated vicious cycle of Alzheimer's disease (AD), intracellular amyloid β (Aβ) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Aβ accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA). Expression of hTFAM significantly improved cognitive function, reducing accumulation of both 8-oxoguanine, an oxidized form of guanine, in mtDNA and intracellular Aβ in 3xTg-AD mice and increasing expression of transthyretin, known to inhibit Aβ aggregation. Next, we found that AD model neurons derived from human induced pluripotent stem cells carrying a mutant PSEN1(P117L)gene, exhibited mitochondrial dysfunction, accumulation of 8-oxoguanine and single-strand breaks in mtDNA, and impaired neuritogenesis with a decreased expression of transthyretin, which is known to be downregulated by oxidative stress. Extracellular treatment with recombinant hTFAM effectively suppressed these deleterious outcomes. Moreover, the treatment increased expression of transthyretin, accompanied by reduction of intracellular Aβ. These results provide new insights into potential novel therapeutic targets.
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Sugako
authors.initials: S
authors.lastname: Oka
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Julio
authors.initials: J
authors.lastname: Leon
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Sakumi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Dongchon
authors.initials: D
authors.lastname: Kang
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003071:Cognition; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D011228:Prealbumin / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C508853:PSEN1 protein, human; D011228:Prealbumin; D053764:Presenilin-1; D017382:Reactive Oxygen Species; C499631:TFAM protein, human; D014157:Transcription Factors