Cerebral amyloidoses: molecular pathways and therapeutic challenges.

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 beta (Abeta) 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 PrP(C), into a beta-sheet rich isoform, named PrP(Sc), which acquires protease-resistance and detergent insolubility. Once generated, Abeta and PrP(Sc) are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Abeta and PrP(Sc) is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Abeta, PrP(Sc) 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 Abeta and PrP(Sc) 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.

• Authors: Salvatore Monaco, Gianluigi Zanusso, Sara Mazzucco, Nicola Rizzuto
• Journal: Current medicinal chemistry (Curr Med Chem) Vol. 13 Issue 16 Pg. 1903-13 ( 2006) ISSN: 0929-8673 [Print] United Arab Emirates
• PMID: 16842201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Amyloid beta-Protein Precursor
• PrPSc Proteins

Topics

• Alzheimer Disease (pathology, therapy)
• Amyloid beta-Protein Precursor (metabolism)
• Amyloidosis (pathology, therapy)
• Animals
• Cerebellar Diseases (pathology, therapy)
• Creutzfeldt-Jakob Syndrome (pathology, therapy)
• Dementia (pathology, therapy)
• Humans
• PrPSc Proteins (metabolism)
• Prion Diseases (pathology, therapy)