title: Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology.
abstract: BACKGROUND
  Increased circulating glucocorticoids are features of both aging and Alzheimer's disease (AD), and increased glucocorticoids accelerate the accumulation of AD pathologies. Here, we analyzed the effects of the glucocorticoid receptor antagonist mifepristone (RU486) in the 3xTg-AD mouse model at an age where hippocampal damage leads to high circulating corticosterone levels.
  
  
  METHODS
  The effects of mifepristone were investigated in 3xTg-AD mice using a combination of biochemical, histological, and behavior analyses.
  
  
  RESULTS
  Mifepristone treatment rescues the pathologically induced cognitive impairments and markedly reduces amyloid beta (Aβ)-load and levels, as well as tau pathologies. Analysis of amyloid precursor protein (APP) processing revealed concomitant decreases in both APP C-terminal fragments C99 and C83 and the appearance of a larger 17-kDa C-terminal fragment. Hence, mifepristone induces a novel C-terminal cleavage of APP that prevents it being cleaved by α- or β-secretase, thereby precluding Aβ generation in the central nervous system; this cleavage and the production of the 17-kDa APP fragment was generated by a calcium-dependent cysteine protease. In addition, mifepristone treatment also reduced the phosphorylation and accumulation of tau, concomitant with reductions in p25. Notably, deficits in cyclic-AMP response element-binding protein signaling were restored with the treatment.
  
  
  CONCLUSIONS
  These preclinical results point to a potential therapeutic role for mifepristone as an effective treatment for AD and further highlight the impact the glucocorticoid system has as a regulator of Aβ generation.
authors: Department of Neurobiology and Behavior, University of California, Irvine, USA.
authors: David
authors: D
authors: Baglietto-Vargas
authors: Rodrigo
authors: R
authors: Medeiros
authors: Hilda
authors: H
authors: Martinez-Coria
authors: Frank M
authors: FM
authors: LaFerla
authors: Kim N
authors: KN
authors: Green
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D050882:CREB-Binding Protein / Q000378:metabolism; D006727:Hormone Antagonists / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006727:Hormone Antagonists; D016875:tau Proteins; D015735:Mifepristone; D050882:CREB-Binding Protein
keywords: 3xTg-AD; Alzheimer's disease; Amyloid beta; glucocorticoids; mifepristone; tau