title: Preplaque ('preclinical') Aβ-induced inflammation and nerve growth factor deregulation in transgenic models of Alzheimer's disease-like amyloid pathology.
abstract: BACKGROUND
  Alzheimer's disease (AD) neuropathology likely begins decades before clinical symptoms are manifested. Investigations on the early stages of the amyloid pathology are crucial for the discovery of diagnostic biomarkers or new therapeutic targets. Our transgenic (tg) animal models are most suitable to study early AD pathological events, as the pathology evolves in a well-staged manner, starting with intracellular Aβ accumulation and ending with plaque deposition.
  
  
  OBJECTIVE
  To determine the occurrence of key inflammatory markers and to look for signs of nerve growth factor (NGF) dysmetabolism at preplaque and postplaque stages in tg models of AD-like amyloid pathology and in human AD brains.
  
  
  METHODS
  We used our own tg lines (mice and rat), high-quality human brain material and applied neurochemical and immunohistochemical experimental approaches.
  
  
  RESULTS
  In both tg models, we observed an intracellular accumulation of oligomeric Aβ in cortical and hippocampal pyramidal neurons. This coincided with an upregulation of key inflammatory markers (iNOS, MHCII, COX-2) and a recruitment of microglia towards Aβ-burdened neurons. Using human AD brains, we showed alterations in the NGF metabolic pathway, which were mirrored in our tg rat model at early and late stages of amyloid plaque generation.
  
  
  CONCLUSIONS
  A proinflammatory process and, consequently, the deregulation of the NGF metabolic pathway could be amongst the earliest pathological events in the progression of AD.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Que, Canada. claudio.cuello@mcgill.ca
authors.forename: A C
authors.initials: AC
authors.lastname: Cuello
authors.forename: M T
authors.initials: MT
authors.lastname: Ferretti
authors.forename: M F
authors.initials: MF
authors.lastname: Iulita
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D002490:Central Nervous System / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D020932:Nerve Growth Factor / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats
chemical_list: D016564:Amyloid beta-Protein Precursor; D011498:Protein Precursors; C061397:pro-nerve growth factor, human; D020932:Nerve Growth Factor; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020780:Matrix Metalloproteinase 9