title: Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease.
abstract: Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized Aβ precursor protein transgenic (AβPP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of Aβ-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric Aβ. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in AβPP primary neurons. We also found an increased accumulation of oligomeric Aβ and increased apoptotic neuronal death in the primary neurons from the AβPP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric Aβ, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AβPP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from Aβ toxicity.
authors.affiliation: Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Calkins
authors.forename: Maria
authors.initials: M
authors.lastname: Manczak
authors.forename: Peizhong
authors.initials: P
authors.lastname: Mao
authors.forename: Ulziibat
authors.initials: U
authors.lastname: Shirendeb
authors.forename: P Hemachandra
authors.initials: PH
authors.lastname: Reddy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001370:Axonal Transport / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008970:Molecular Weight; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D054464:Peroxiredoxins / Q000378:metabolism; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D000081406:Peptidyl-Prolyl Isomerase F; D009842:Oligopeptides; C000631446:PPIF protein, mouse; D012333:RNA, Messenger; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D003576:Electron Transport Complex IV; D021983:Cyclophilins