title: Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus.
abstract: BACKGROUND
  Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer's patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice.
  
  
  RESULTS
  Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes.
  
  
  CONCLUSIONS
  A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Cientificas Universidad de Sevilla, Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Torres
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jimenez
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Varo
authors.forename: Victoria
authors.initials: V
authors.lastname: Navarro
authors.forename: Laura
authors.initials: L
authors.lastname: Trujillo-Estrada
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sanchez-Mejias
authors.forename: Irene
authors.initials: I
authors.lastname: Carmona
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Davila
authors.forename: Marisa
authors.initials: M
authors.lastname: Vizuete
authors.forename: Antonia
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
mesh_terms: D000375:Aging / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor