Displacement toward NFT of a key enzyme of the ubiquitin proteolytic pathway in Alzheimer's brain

Abstract

Recent findings have led to a better understanding of the roles of the ubiquitin (Ub) proteasome system in the progression of different human degenerative diseases. The neuropathological hallmarks of Alzheimer's disease (AD) are the neurofibrillary tangles (NFT) and the senile plaques (SP). NFT accumulate within neurons and are composed of filamentous aggregates (PHF) of the microtubule‐associated protein tau (Layfield 2001). The intraneuronal inclusions contain deposits of ubiquitylated proteins, indicating that perturbations of Ub‐dependent proteolysis may be occurring. We have demonstrated the existence of a defective ubiquitination in the cytosol of AD brains, due to a decrease in normal Ub activating enzyme (E1) activity in the cytosol as a consequence of its de‐localization to the particulate fraction (Lopez Salon 2000). Immunohistochemical experiments using an antibody against PHF, showed a great number of NFT in AD. Using an anti E1 antibody we demonstrated the presence of this enzyme in the NFT. In order to corroborate the above mentioned results, we have carried out biochemical studies to investigate the pattern of solubilization of the proteins present in NFT in different fractions isolated by differential centrifugation. In AD almost 60% of E1 is obtained in a particulate fraction, while in control samples E1 is mainly located at the supernatant. The de‐localization of E1 could be a late event occurring during the progression of AD. A secondary impairment of Ub‐dependent degradation due to a decrease in normal E1 activity in the brain cytosol may contribute to the abnormal accumulation of proteins in AD and deserves future research as a possible disease mechanism.