title: Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons.
abstract: BACKGROUND
  Synaptic dysfunction and intracellular transport defects are early events in Alzheimer's disease (AD). Extracellular amyloid β (Aβ) oligomers cause spine alterations and impede the transport of proteins and organelles such as brain-derived neurotrophic factor (BDNF) and mitochondria that are required for synaptic function. Meanwhile, intraneuronal accumulation of Aβ precedes its extracellular deposition and is also associated with synaptic dysfunction in AD. However, the links between intracellular Aβ, spine alteration, and mechanisms that support synaptic maintenance such as organelle trafficking are poorly understood.
  
  
  RESULTS
  We compared the effects of wild-type and Osaka (E693Δ)-mutant amyloid precursor proteins: the former secretes Aβ into extracellular space and the latter accumulates Aβ oligomers within cells. First we investigated the effects of intracellular Aβ oligomers on dendritic spines in primary neurons and their tau-dependency using tau knockout neurons. We found that intracellular Aβ oligomers caused a reduction in mushroom, or mature spines, independently of tau. We also found that intracellular Aβ oligomers significantly impaired the intracellular transport of BDNF, mitochondria, and recycling endosomes: cargoes essential for synaptic maintenance. A reduction in BDNF transport by intracellular Aβ oligomers was also observed in tau knockout neurons.
  
  
  CONCLUSIONS
  Our findings indicate that intracellular Aβ oligomers likely contribute to early synaptic pathology in AD and argue against the consensus that Aβ-induced spine loss and transport defects require tau.
authors: Department of Neuroscience, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors: Tomohiro
authors: T
authors: Umeda
authors: Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada.
authors: Elisa M
authors: EM
authors: Ramser
authors: Department of Neuroscience, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.
authors: Minato
authors: M
authors: Yamashita
authors: Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Koichi
authors: K
authors: Nakajima
authors: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.|Department of Clinical Neuroscience, Osaka City University Medical School, Osaka, Japan.
authors: Hiroshi
authors: H
authors: Mori
authors: Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada. masilver@sfu.ca.
authors: Michael A
authors: MA
authors: Silverman
authors: Department of Neuroscience, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan. tomi@med.osaka-cu.ac.jp.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan. tomi@med.osaka-cu.ac.jp.
authors: Takami
authors: T
authors: Tomiyama
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000648:ultrastructure*; D015388:Organelles / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D014162:Transfection; D016875:tau Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; C558298:Mapt protein, mouse; C485184:enhanced green fluorescent protein; D016875:tau Proteins; D049452:Green Fluorescent Proteins