title: Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.
abstract: BACKGROUND
  Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing.
  
  
  RESULTS
  The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks.
  
  
  CONCLUSIONS
  Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.
authors.affiliation: INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.|Université Paris Descartes, Paris, France.|CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Audrain
authors.affiliation: INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.|Université Paris Descartes, Paris, France.|CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Fol
authors.affiliation: INSERM UMR894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutar
authors.affiliation: INSERM UMR894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Potier
authors.affiliation: INSERM UMR894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Billard
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.|INSERM UMS27, Fontenay-aux-Roses 92265, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Flament
authors.affiliation: INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.|CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.affiliation: INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.|Université Paris Descartes, Paris, France.|CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Burlot
authors.affiliation: INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.|CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Dufayet-Chaffaud
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.|CNRS UMR9199, Fontenay-aux-Roses 92265, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.
authors.forename: Alexis-Pierre
authors.initials: AP
authors.lastname: Bemelmans
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.|CNRS UMR9199, Fontenay-aux-Roses 92265, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Valette
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.|INSERM UMS27, Fontenay-aux-Roses 92265, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.|CNRS UMR9199, Fontenay-aux-Roses 92265, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.affiliation: Department of Clinical Neurosciences, Laboratory of Cellular and Molecular Neurotherapies, Lausanne University Hospital, Lausanne, Switzerland.|Neuroscience Research Center, Laboratory of Cellular and Molecular Neurotherapies, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.affiliation: INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France. nathalie.cartier@inserm.fr.|CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France. nathalie.cartier@inserm.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
authors.affiliation: INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.|CEA, DSV, I2BM, MIRCen, Fontenay-aux-Roses, 92265, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Braudeau
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D058225:Plaque, Amyloid / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins