ADAM proteases: protective role in Alzheimer's and prion diseases?
Alzheimer's disease, as well as most of other neurodegenerative disorders, is characterized by the deposition of insoluble proteinaceous aggregates. Hence, any intervention aimed at reducing this process could be envisioned as a therapeutic way to slow down the disease. In the case of Alzheimer's disease, the culprit protein is the 40-43 amino acid-long amyloid beta peptide (Abeta). This fragment is generated from the beta-amyloid precursor protein (betaAPP) by two distinct enzymes, namely the beta- and the gamma-secretases. In the past years, a tremendous effort has been made to develop potent and specific inhibitors of these proteolytic activities. Beside these Abeta-forming proteases, a third cleavage performed by the so-called alpha-secretase takes place in the middle of the Abeta sequence and not only precludes its formation but also generates the secreted product sAPPalpha that possesses neurotrophic and neuroprotective properties. This beneficial cleavage has been shown to be strongly upregulated by protein kinase C (PKC) agonists and to be, at least partially, triggered by ADAM proteases (A Disintegrin And Metalloprotease). Recently, a proteolytic attack with similar characteristics has been shown to occur in the middle of the "toxic" 106-126 domain of the prion protein (PrPc), which PrPsc isoform is the causative agent of transmissible spongiform encephalopathies. As both Abeta and PrP(106-126) trigger neurotoxicity and cell death, this ADAM-dependent proteolytic attack could represent a valuable therapeutic target in order to deplete cells from these endogenous "toxins"and prevent the associated aggregates usually detected in affected brains.
Vincent
Bruno
B
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, 660 route des Lucioles, 06560 Valbonne, France. vincentb@ipmc.cnrs.fr
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D019483:Disintegrins / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism*
D019483:Disintegrins; D018696:Neuroprotective Agents; D008666:Metalloendopeptidases