title: Facilitation of brain mitochondrial activity by 5-aminolevulinic acid in a mouse model of Alzheimer's disease.
abstract: The activities of mitochondrial enzymes, which are essential for neural function, decline with age and in age-related disease. In particular, the activity of cytochrome c oxidase (COX/complex IV) decreases in patients with Alzheimer's disease (AD). COX, a mitochondrial inner membrane protein complex that contains heme, plays an essential role in the electron transport chain that generates ATP. Heme synthesis begins with 5-aminolevulinic acid (5-ALA) in mitochondria. 5-ALA synthetase is the rate-limiting enzyme in heme synthesis, suggesting that supplementation with 5-ALA might help preserve mitochondrial activity in the aged brain. We administered a diet containing 5-ALA to triple-transgenic AD (3xTg-AD) model mice for 6 months, starting at 3 months of age. COX activity and protein expression, as well as mitochondrial membrane potential, were significantly higher in brains of 5-ALA-fed mice than in controls. Synaptotagmin protein levels were also significantly higher in 5-ALA-fed mice, suggesting improved preservation of synapses. Although brain Aβ levels tended to decrease in 5-ALA-fed mice, we observed no other significant changes in other biochemical and pathological hallmarks of AD. Nevertheless, our study suggests that daily oral administration of 5-ALA could preserve mitochondrial enzyme activities in the brains of aged individuals, thereby contributing to the preservation of neural activity.
authors.affiliation: a Department of Integrated Bioscience , Graduate School of Frontier Sciences, The University of Tokyo , Kashiwa 277-8562 , Japan.|b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Chiori
authors.initials: C
authors.lastname: Omori
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Motodate
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Yuzuha
authors.initials: Y
authors.lastname: Shiraki
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Chiba
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Sobu
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Kimura
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.affiliation: c SBI Pharmaceuticals Co., Ltd , Tokyo 106-6020 , Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kondo
authors.affiliation: c SBI Pharmaceuticals Co., Ltd , Tokyo 106-6020 , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kurumiya
authors.affiliation: c SBI Pharmaceuticals Co., Ltd , Tokyo 106-6020 , Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: a Department of Integrated Bioscience , Graduate School of Frontier Sciences, The University of Tokyo , Kashiwa 277-8562 , Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: c SBI Pharmaceuticals Co., Ltd , Tokyo 106-6020 , Japan.
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: b Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences , Hokkaido University , Sapporo 060-0812 , Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Hata
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000622:Aminolevulinic Acid / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018697:Nootropic Agents / Q000627:therapeutic use*; D012727:Sex Characteristics; D050857:Synaptotagmins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D050857:Synaptotagmins; D000622:Aminolevulinic Acid; D003576:Electron Transport Complex IV
keywords: 5-Aminolevulinic acid; Aging; Alzheimer's disease; Amyloid-β; Cytochrome c oxidase; Synaptotagmin