Author: Bruno Vincent

Source: Current Alzheimer Research, Volume 1, Number 3, August 2004 , pp. 165-174(10)

Publisher: Bentham Science Publishers

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). This fragment is generated from the -amyloid precursor protein (bAPP) by two distinct enzymes, namely the - 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-forming proteases, a third cleavage performed by the socalled -secretase takes place in the middle of the A sequence and not only precludes its formation but also generates the secreted product sAPP 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: http://dx.doi.org/10.2174/1567205043332072

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

Publication date: 2004-08-01

More about this publication?

• Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

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