Role of the proteasome in Alzheimer's disease

The proteasome is a multicatalytic complex involved in the degradation of polyubiquitinated proteins. Here we review the clues of a possible involvement of the proteasome in Alzheimer's disease neuropathology. Thus, we discuss the fact that the proteasome modulates the intracellular concentrations of presenilins 1 and 2. These two proteins, when mutated, appear responsible for most of early onset forms of Alzheimer's disease and this is thought to be due to the exacerbation of the pathogenic pathway of the maturation of the beta-amyloid precursor protein. Controlling presenilins concentrations could have drastic repercussions on cell physiology as suggested by the fact that proteasome inhibitors drastically potentiate the 'normal' or 'pathogenic' presenilins phenotype related with beta APP processing. The possibility of considering the proteasome as a potential tar-get for therapeutic intervention ill Alzheimer's disease is discussed. (C) 2000 Elsevier Science B.V. All rights reserved.