IngentaConnect ADAM Proteases: Protective Role in Alzheimers and Prion Diseases ...

Abstract:

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 acidlong amyloid b peptide (A bgr

). This fragment is generated from the bgr

-amyloid precursor protein (bAPP) by two distinct enzymes, namely the bgr

- and the

-secretases. In the past years, a tremendous effort has been made to develop potent and specific inhibitors of these proteolytic activities. Beside these A bgr

-forming proteases, a third cleavage performed by the socalled agr

-secretase takes place in the middle of the A bgr

sequence and not only precludes its formation but also generates the secreted product sAPP agr

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 “toxicrdquo; 106-126 domain of the prion protein (PrPc), which PrPsc isoform is the causative agent of transmissible spongiform encephalopathies. As both Ab 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.

Keywords: ADAM Proteases; 40-43 amino acidlong; protein kinase C (PKC); encephalopathies; prion protein (PrPc)

Document Type: Review article

DOI: 10.2174/1567205043332072

Affiliations: 1: Institut de Pharmacologie Moleculaire et Cellulaire, CNRS UMR 6097, 660 route des Lucioles, 06560 Valbonne, France.

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ADAM Proteases: Protective Role in Alzheimer's and Prion Diseases ?