NR AUZK
AU Monaco,S.; Zanusso,G.; Mazzucco,S.; Rizzuto,N.
TI Cerebral amyloidoses: molecular pathways and therapeutic challenges.
QU Current Medicinal Chemistry 2006; 13(16): 1903-13
PT journal article; review
AB 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 PrPc, into a beta-sheet rich isoform, named PrPsc, which acquires protease-resistance and detergent insolubility. Once generated, Abeta and PrPsc are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Abeta and PrPsc is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Abeta, 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 Abeta 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.
ZR 100
MH 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; Research Support, Non-U.S. Gov't
AD Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona, Ospedale G.B. Rossi, Piazzale L.A. Scuro, 10, I-37134, Verona, Italy. salvatore.monaco@univr.it
SP englisch
PO Niederlande