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تسجيل مستخدم جديدADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimers Disease
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Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amy-loid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimers disease brains. Accordingly, in vitro down-or up-regulation of ADAM30 expression triggered an increase/decrease in A$beta$ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30 mut) did not affect A$beta$ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered A$beta$42 secretion in neuron primary cultures, soluble A$beta$42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation.
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Currently, many studies of Alzheimers disease (AD) are investigating the neurobiological factors behind the acquisition of beta-amyloid (A), pathologic tau (T), and neurodegeneration ([N]) biomarkers from neuroimages. However, a system-level mechanis
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