ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease
Abstract
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 Alzheimer's disease brains. Accordingly, in vitro down-or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30 mut) did not affect Aβ 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 Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation Keywords: Alzheimer APP ADAM30 Amyloid Metabolism LTP EBioMedicine 9 (2016) 278-292 Abbreviations: ADAM, A Disintegrin and Metalloproteinase Domain; APP, amyloid precursor protein; BACE, Beta-site APP cleaving enzyme 1; BSA, bovine serum albumin; CamKIIα, Ca2+/calmodulin-dependent protein kinase II alpha; COFRADIC, combined fractional diagonal chromatography; CTSD, cathepsin D; GKAP1, G kinase-anchoring protein 1; IRS4, insulin receptor substrate 4; LTP, long term potentiation; MMP, metalloproteinase; MRI, magnetic resonance imaging; PLA, proximity ligation assay; TD2, Type 2 diabetes. ⁎
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Neurons and Cognition [q-bio.NC]
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