Beta-amyloid production, aggregation, and clearance as targets for therapy in Alzheimer's disease.
1. Despite major efforts aimed at elucidating the molecular basis and physiopathology of Alzheimer's disease (AD), there is still no effective treatment available for this devastating disorder. The biological mechanisms underlying the development of AD are complex, as multiple factors appear to modulate (either positively or negatively) the progression of neurodegeneration in the brains of AD patients. Not surprisingly, a number of different therapeutic approaches aimed at distinct aspects of the disease are currently being pursued. Given its central role in the neuropathology of AD, the beta-amyloid peptide (Abeta) is the focus of many such approaches. 2. In this review, we discuss recent developments along three major lines of investigation: (i) identification and characterization of inhibitors of the enzymes involved in proteolytic processing of the amyloid precursor protein and production of Abeta; (ii) identification of the pathways involved in cerebral degradation and clearance of Abeta; and (iii) characterization of small-molecule inhibitors of amyloid aggregation that prevent cerebral amyloid deposition and neurotoxicity. 3. Significant progress has been achieved in these directions, opening up new perspectives toward the development of effective approaches for the treatment or prevention of AD.
De Felice
Fernanda G
FG
Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil. felice@bioqmed.ufrj.br
Ferreira
Sérgio T
ST
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000493:pharmacokinetics; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D046911:Macromolecular Substances; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D010447:Peptide Hydrolases