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Cerebral Amyloidoses: Molecular Pathways and Therapeutic Challenges

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Abstract:

Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are sporadic and genetic neurodegenerative conditions characterized by brain accumulation and deposition of protein aggregates. In AD, the key pathogenic event is linked to the formation of a 4-kDa amyloid β (Aβ) peptide, generated by sequential cleavages of the amyloid precursor protein (APP). In CJD and other prion diseases, the process is initiated by conformational changes of the cellular prion protein, or PrPC, into a β-sheet rich isoform, named PrPsc, which acquires protease-resistance and detergent insolubility. Once generated, Aβ and PrPsc are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Aβ and PrPsc is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Aβ, PrPsc is also infectious, and this feature poses public health concerns, as in the case of iatrogenic and variant CJD (vCJD).

Several lines of evidence suggest that Aβ and PrPsc are the main factors responsible for death of selected neuronal populations in brains of AD and prion disease's victims. Therefore, in addition to symptomatic treatment of dementia, therapeutic efforts are currently aimed at testing the efficacy of disease-modifying, anti-amyloid therapies. Experimental and clinical therapeutic interventions include passive and active immunization against amyloidogenic peptides, non immunological strategies, as well as drugs enhancing the nonamyloidogenic protein processing. In this review, we focus on molecular mechanisms of AD and prion diseases, and on novel treatment approaches.



Keywords: Alzheimer disease; Creutzfeldt-Jakob disease; amyloid precursor protein; anti-amyloid therapies; dementia; prion diseases; protein-misfolding diseases; transmissible spongiform encephalopathies

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986706777585022

Affiliations: Department of Neurological and Visual Sciences, University of Verona, Ospedale G.B.Rossi, Piazzale L.A. Scuro, 10, I-37134, Verona, Italy.

Publication date: July 1, 2006

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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