The ubiquitin-proteasome system in Alzheimer's disease

Abstract

Accumulation of proteins is a recurring event in many neurodegenerative diseases, including Alzheimer's disease (AD). Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS). Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD. This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Abeta and tau, the two hallmark lesions of AD, and the UPS.

1

Early evidence of proteasomal dysfunction in AD demonstrated the presence of ubiquitin-positive structures in AD brains. Representative microphotographs showing that ubiquitinated proteins are associated with amyloid plaques (A) and neurofibrillary tangles (B) in AD brains.

2

Schematic representation of a possible scenario by which Aβ can mediate tau accumulation via the pro-teasome. During normal conditions, ubiquitinated tau is targeted to the proteasome for turnover (A). Aβ deposit can inhibit the proteasome impairing its normal function. As a consequence, tau cannot be degraded by the pro-teasome and accumulates into NFT (B).