title: Tau pathogenesis is promoted by Aβ1-42 but not Aβ1-40.
abstract: BACKGROUND
  The relationship between the pathogenic amyloid β-peptide species Aβ1-42 and tau pathology has been well studied and suggests that Aβ1-42 can accelerate tau pathology in vitro and in vivo. The manners if any in which Aβ1-40 interacts with tau remains poorly understood. In order to answer this question, we used cell-based system, transgenic fly and transgenic mice as models to study the interaction between Aβ1-42 and Aβ1-40.
  
  
  RESULTS
  In our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to Aβ1-42 induced cleavage, phosphorylation and aggregation of wild-type/full length tau while exposure to Aβ1-40 didn't. Functional studies with Aβ1-40 were carried out in tau-GFP transgenic flies and showed that Aβ1-42, as previously reported, disrupted cytoskeletal structure while Aβ1-40 had no effect at same dose. To further explore how Aβ1-40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either Aβ1-42 or Aβ1-40. We found that treatment with Aβ1-42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice. By contrast, Aβ1-40 injection didn't alter total tau, phospho-tau (recognized by PHF-1) or cleavage of tau, but interestingly, phosphorylation at Ser262 was shown to be significantly decreased after direct inject of Aβ1-40 into the entorhinal cortex of P301S mice.
  
  
  CONCLUSIONS
  These results demonstrate that Aβ1-40 plays different role in tau pathogenesis compared to Aβ1-42. Aβ1-40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser262, which has been shown to be neurotoxic.
authors.affiliation: Appel Alzheimer's Disease Research Institute, Weill Cornell Medical College, 413 East 69th Street, 10th Floor, BB 1051, mailbox #240, New York, NY 10065, USA. xih2006@med.cornell.edu.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Mingrui
authors.initials: M
authors.lastname: Zhao
authors.forename: Andrew
authors.initials: A
authors.lastname: Gottesdiener
authors.forename: Wenjie
authors.initials: W
authors.lastname: Luo
authors.forename: Steven
authors.initials: S
authors.lastname: Paul
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D005838:Genotype; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C558298:Mapt protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins