Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression

作者：Audrain Mickael; Fol Romain; Dutar Patrick; Potier Brigitte; Billard Jean Marie; Flament Julien; Alves Sandro; Burlot Marie Anne; Dufayet Chaffaud Gaelle; Bemelmans Alexis Pierre; Valette Julien; Hantraye Philippe; Deglon Nicole; Cartier Nathalie^*; Braudeau Jerome

来源：Molecular Neurodegeneration, 2016, 11(1): 5.

DOI：10.1186/s13024-016-0070-y

• Alzheimer's disease early stages
• A beta ratio
• Human samples
• Animal model
• Extrasynaptic NMDAR
• Synaptic failure

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, beta CTF and A beta 42/40 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 (1H-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, beta CTF and A beta 42/A beta 40 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.

• 出版日期2016-1-12
• 单位中国地震局