title: Soluble Conformers of Aβ and Tau Alter Selective Proteins Governing Axonal Transport.
abstract: Despite the demonstration that amyloid-β (Aβ) can trigger increased tau phosphorylation and neurofibrillary tangle (NFT) formation in vivo, the molecular link associating Aβ and tau pathologies remains ill defined. Here, we observed that exposure of cultured primary neurons to Aβ trimers isolated from brain tissue of subjects with Alzheimer's disease led to a specific conformational change of tau detected by the antibody Alz50. A similar association was supported by postmortem human brain analyses. To study the role of Aβ trimers in vivo, we created a novel bigenic Tg-Aβ+Tau mouse line by crossing Tg2576 (Tg-Aβ) and rTg4510 (Tg-Tau) mice. Before neurodegeneration and amyloidosis, apparent Aβ trimers were increased by ∼2-fold in 3-month-old Tg-Aβ and Tg-Aβ+Tau mice compared with younger mice, whereas soluble monomeric Aβ levels were unchanged. Under these conditions, the expression of soluble Alz50-tau conformers rose by ∼2.2-fold in the forebrains of Tg-Aβ+Tau mice compared with nontransgenic littermates. In parallel, APP accumulated intracellularly, suggestive of a putative dysfunction of anterograde axonal transport. We found that the protein abundance of the kinesin-1 light chain (KLC1) was reduced selectively in vivo and in vitro when soluble Aβ trimers/Alz50-tau were present. Importantly, the reduction in KLC1 was prevented by the intraneuronal delivery of Alz50 antibodies. Collectively, our findings reveal that specific soluble conformers of Aβ and tau cooperatively disrupt axonal transport independently from plaques and tangles. Finally, these results suggest that not all endogenous Aβ oligomers trigger the same deleterious changes and that the role of each assembly should be considered separately.
  
  
  
  The mechanistic link between amyloid-β (Aβ) and tau, the two major proteins composing the neuropathological lesions detected in brain tissue of Alzheimer's disease subjects, remains unclear. Here, we report that the trimeric Aβ species induce a pathological modification of tau in cultured neurons and in bigenic mice expressing Aβ and human tau. This linkage was also observed in postmortem brain tissue from subjects with mild cognitive impairment, when Aβ trimers are abundant. Further, this modification of tau was associated with the intracellular accumulation of the precursor protein of Aβ, APP, as a result of the selective decrease in kinesin light chain 1 expression. Our findings suggest that Aβ trimers might cause axonal transport deficits in AD.
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55414.
authors.forename: Mathew A
authors.identifier: 0000-0002-0986-5815
authors.initials: MA
authors.lastname: Sherman
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55414.
authors.forename: Michael
authors.initials: M
authors.lastname: LaCroix
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55414.
authors.forename: Fatou
authors.initials: F
authors.lastname: Amar
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55414.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Larson
authors.affiliation: N. Bud Grossman Center for Memory Research and Care.
authors.forename: Colleen
authors.identifier: 0000-0001-5593-882X
authors.initials: C
authors.lastname: Forster
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich 8091, Switzerland, and.
authors.forename: Adriano
authors.identifier: 0000-0002-0344-6708
authors.initials: A
authors.lastname: Aguzzi
authors.affiliation: Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: N. Bud Grossman Center for Memory Research and Care.
authors.forename: Martin
authors.initials: M
authors.lastname: Ramsden
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55414, lesne002@umn.edu.
authors.forename: Sylvain E
authors.identifier: 0000-0001-9411-1868
authors.initials: SE
authors.lastname: Lesné
mesh_terms: D000328:Adult; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D006801:Humans; D016547:Kinesins; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D011487:Protein Conformation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000715688:KLC1 protein, human; C000715695:Kns2 protein, mouse; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D016547:Kinesins
keywords: Alzheimer's disease; amyloid-beta; axonal transport; brain; oligomer; tau