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Rôle des ADAM dans le processus physiopathologique de la maladie d'Alzheimer

Abstract : Alzheimer’s disease (AD) is the most common neurodegenerative disorder of the old age, characterized by the presence of two major neuropathological features : neurofibrillary tangles and senile plaques. These plaques are composed of the Aβ peptides cleavage product of the amyloid precursor protein (APP). Proteolytic processing of APP is modulated by the action of enzymes α-, β- and γ-secretases with the latter two mediating the amyloidogenic pathway. Suggesting that processing of APP is a key step in the pathology of AD. However, even if extensively studied, this APP metabolism is still not fully characterized. With this background, we postulate that the characterization of new actors of the APP metabolism might help for a more subtle understanding of this APP metabolism and trafficking. We focused on the ADAMs and related proteins with the hypothesis that ADAMs and related proteins, under- or over-expressed in the brain of AD cases compared with the one of controls, may be of particular interest. Beyond the obvious implication of several ADAMs as α-secretases, this hypothesis was also driven by several observations : (i) ADAMs have been involved in numerous biological processes including brain development, plasticity and repair as APP; (ii) several metalloproteases (MMP-2, -3 and -9) have been described to degrade Aβ peptides. Using microarray to screen the expression of 117 ADAMs and MMPs was analyzed using total RNA extracted from cerebral tissue of 12 AD cases and 12 controls. We observed that 4 ADAMs were differentially expressed. We first confirmed that the ADAM30 expression was decreased in AD brains and we observed that ADAM30 under-expression was correlated with an increase in Aβ42 deposition in AD brains. Consistently, over-expression of ADAM30 led to decrease APP metabolism and as a consequence, Aβ secretion in two different cell lines (Moreover, under-expressed ADAM30 increases APP processing and Aβ generation). This modification of the APP metabolism was directly linked to the ADAM30 catalytic properties. Our data suggest that catalytic activity of ADAM30 takes an important place in APP processing in a lysosome dependent manner and AD pathophysiological process.
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Submitted on : Monday, March 14, 2011 - 2:46:15 PM
Last modification on : Wednesday, October 14, 2020 - 4:10:57 AM
Long-term archiving on: : Wednesday, June 15, 2011 - 3:02:13 AM


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  • HAL Id : tel-00576504, version 1



Geoffroy Laumet. Rôle des ADAM dans le processus physiopathologique de la maladie d'Alzheimer. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2010. Français. ⟨NNT : 2010LIL2S032⟩. ⟨tel-00576504⟩



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