Yes / A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling. / Wellcome Trust, Grant/Award Number: 200646/Z/16/Z

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Depuis quelques années, les oligomères du peptide Aβ sont identifiés comme étant responsables du déclenchement de la pathologie alors que les dépôts amyloïdes sont des conséquences aggravantes de la pathologie. Cependant, les formes oligomériques d’Aβ impliquées dans la pathologie ainsi que l’origine de ces peptides sont toujours débattues. Notre objectif principal était d’identifier des signatures Aβ oligomériques cérébrales et vasculaires et de déterminer si nous pouvions interférer avec ces signatures pour modifier le décours de la pathologie. Nous avons réalisé des analyses biochimiques qualitative des formes d’Aβ dans des échantillons de cerveau et de vaisseaux issus de patients atteints de la MA et de souris transgéniques modèle de la MA. Nous avons montré qu’une même forme Aβ oligomérique (17-18 kDa) est impliquée dans le développement de la pathologie cognitive chez l’homme et chez la souris APP/PS1. Une signature Aβ oligomérique vasculaire spécifique a été observée dans les vaisseaux périphériques et plus particulièrement la veine porte hépatique des souris APP/PS1. De plus, un traitement pharmacologique ciblant l’expression des protéines de transport de l’Aβ a permis de restaurer les profils Aβ oligomériques contrôles dans le cerveau des souris APP/PS1 tout en « chargeant » la veine porte des mêmes souris en Aβ oligomérique. Ces résultats montrent que les signatures Aβ vasculaires et cérébrales sont intimement liées. De plus, nos travaux mettent l’accent sur une possible intervention thérapeutique agissant sur les formes Aβ cérébrales et vasculaires. / Alzheimer's disease (AD) is a complex disorder of the central nervous system that affects an increasing number of people worldwide due to the overall aging of the human population. Vascular factors and mechanisms have emerged as an area of key importance. Accumulating evidence indicates that pre-fibrillar aggregates, specifically the low-molecular weight oligomers of Aβ peptide, are responsible for the synaptic dysfunction and neuronal loss that occur in AD pathology. But, these oligomeric forms implicated in the pathology are currently under debate. Our primary goal was to identify cerebral and vascular oligomeric signatures. Secondly, we try to interfere with these signatures in order to modify the evolution of AD. We realize qualitative analyses of cerebral and vascular oligomers Aβ by western-blot. Vascular and cerebral tissues were extracted from AD patients and from a transgenicmouse model of AD. We demonstrate that the same oligomer Aβ (17-18 kDa) is implicated in the cognitive impairment for patients and APP/PS1 mouse. A specific vascular signature of oligomer Aβ was detected in peripheral vessels and particularly in portal vein from liver of APP/PS1 mouse. Moreover, pharmacological treatment targeting clearance of soluble Aβ restored the control signature of oligomer Aβ in the brain of APP/PS1 mouse. This configurational change was associated with an increase of oligomer Aβ in portal vein from liver. These results show that cerebral and vascular oligomeric signatures were closely linked. Finally, our work emphasizes potential therapeutic strategies for AD by targeting cerebrals and vasculars oligomers Aβ.